The vascular perspective on acute and chronic lung disease

The pulmonary vasculature has been frequently overlooked in acute and chronic lung diseases, such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis (PF), and chronic obstructive pulmonary disease (COPD). The primary emphasis in the management of these parenchymal disorders has largely revolved around the injury and aberrant repair of epithelial cells. However, there is increasing evidence that the vascular endothelium plays an active role in the development of acute and chronic lung diseases. The endothelial cell network in the capillary bed and the arterial and venous vessels provides a metabolically highly active barrier that controls the migration of immune cells, regulates vascular tone and permeability, and participates in the remodeling processes. Phenotypically and functionally altered endothelial cells, and remodeled vessels, can be found in acute and chronic lung diseases, although to different degrees, likely because of disease-specific mechanisms. Since vascular remodeling is associated with pulmonary hypertension, which worsens patient outcomes and survival, it is crucial to understand the underlying vascular alterations. In this Review, we describe the current knowledge regarding the role of the pulmonary vasculature in the development and progression of ARDS, PF, and COPD; we also outline future research directions with the hope of facilitating the development of mechanism-based therapies.

ARDS can be caused by direct trauma, such as exposure to toxic substances or respiratory infections, as well as by indirect insults like sepsis (4, 5). ARDS is accompanied by severe inflammation and pulmonary vascular dysfunction with diffuse microvascular damage. Pathological changes that develop early in the disease course, e.g., pulmonary vasoconstriction, edema, hypoxemia, embolic vascular obliteration, and capillary damage, can increase pulmonary resistance and cause PH. Studies by Lynne Reid in the 1970s and 1980s showed vascular involvement in patients with ARDS (6, 7). Subsequent studies have since verified the profound vascular damage in ARDS (8–11). As ARDS progresses, there is a loss of capillary density (6) along with SMC hypertrophy and neomuscularization, leading to media thickening (12). However, the long-term effects of ARDS on pulmonary vascular function have not been extensively studied.

Vascular involvement is a common feature of ARDS, particularly in cases of severe COVID-19 (13). Lungs from patients with COVID-19–associated ARDS exhibit pronounced endothelial inflammation including severe endothelial damage, vascular leak, and widespread thrombosis (14). Interestingly, senescent ECs seem to exhibit heightened susceptibility to SARS-CoV-2 infection and subsequent endothelial dysfunction (15). This observation is intriguing, especially since people over 65, who are more likely to have senescent ECs and comorbidities associated with endothelial dysfunction (16, 17), are at higher risk of developing severe COVID-19.

Using single-cell RNA sequencing, multiple lung EC phenotypes have been identified, each potentially playing a unique role in the development of ARDS (18). In the context of virus-induced lung injury, carbonic anhydrase 4–positive (Car4-positive) ECs localize to lung regenerative regions, demonstrating the potential to respond to reparative signals from alveolar type I cells. Furthermore, a highly proliferating EC subpopulation was observed, likely contributing to alveolar revascularization (19). Cumulatively, these findings underscore the multifaceted contributions of ECs in the disease process and reestablishment of lung homeostasis following injury.

Multifactorial mechanisms of endothelial dysfunction in ARDS

An ongoing inflammatory response and increased oxidative stress cause endothelial injury leading to vessel permeability. This process is further compounded by the release of interstitial proinflammatory mediators into the bloodstream, which attract additional immune cells to the site of injury and perpetuate the inflammatory cycle (Figure 1). Various mechanisms involved in endothelial dysfunction, including the inflammatory response, the cellular stress response, and the fibroproliferative response, offer potential avenues for future therapeutic investigations.

Figure 1

Mechanisms of endothelial dysfunction. Endothelial cell (EC) injury can occur through a variety of stressors, such as cigarette smoke (CS), inflammation, and oxidative stress, leading to an activated and inflamed EC, which may manifest as ER stress and/or p53 dysregulation, or Cav-1 downregulation. Deregulation of transcription factors, such as FOXF1 or ERG, promotes a fibrosis-conducive EC phenotype. Inflamed ECs express a variety of adhesion molecules, further contributing to the recruitment of inflammatory cells. If uncontrolled, aberrant regulation of these processes can lead to a vicious cycle of sustained inflammation and tissue destruction. EC injury can also induce cellular senescence, advancing tissue inflammation, myofibroblast formation, and remodeling via a senescence-associated secretory phenotype (SASP). The extent to which proliferating EC precursors can substitute injured ECs and restore EC homeostasis still needs to be determined.

Inflammatory response. An activated endothelium expresses higher levels of platelet and leukocyte adhesion molecules, including E-selectin, P-selectin, ICAM-1, and VCAM-1 (20, 21), leading to a procoagulant and immunoreactive phenotype and fibrin deposition (22). The interaction of platelets with neutrophils results in reciprocal activation and drives so-called immunothrombosis (23). The procoagulation state in ARDS has been the focus of several therapeutic approaches. However, systemic administration of recombinant human-activated protein C (24), antithrombin (25), and tifacogin (tissue factor pathway inhibitor; ref. 25) all yielded disappointing clinical outcomes, proving modulation of disturbed coagulation in patients with ARDS to be a challenging target.

During the inflammatory response, neutrophils are recruited to the site of injury, where they release neutrophil elastase (NE). NE proteolytic activity has been shown to damage protective, endothelial glycocalyx (26) and to degrade ECM proteins, releasing growth factors bound to the ECM, and activating other proteases and inflammatory mediators, thereby amplifying the inflammatory response and tissue damage (27). Considering the central role of neutrophil-mediated vascular injury in the development of vascular dysfunction, inhibiting the proteolytic activity of NE could provide a plausible strategy for preserving vascular integrity. Indeed, clinical trials regarding the use of NE inhibitor in treating ARDS are currently being conducted (Table 1).

Table 1

Clinical trials testing vessel-aimed therapy in acute and chronic lung diseases

Another important regulator of pulmonary vascular homeostasis is caveolin-1 (Cav-1), which has been implicated in ARDS and CLDs. This scaffolding protein plays a crucial role in structural support and cellular signaling, contributing to the overall integrity and functionality of the pulmonary vasculature (28). In ARDS lung tissue, a noticeable reduction in Cav-1 expression occurs specifically in the endothelial layer of remodeled vessels (11). Cav1^–/– mice develop pronounced lung abnormalities, including hypercellularity, alveolar wall thickening, extensive pulmonary vascular remodeling, and PH (29, 30). These observations suggest that the deregulation of Cav-1 might be an important initiating factor in EC dysfunction, ultimately leading to vascular remodeling.

Cellular stress response. In ARDS, various stressors cause endoplasmic reticulum (ER) stress, which is central to endothelial dysfunction. The unfolded protein response (UPR) helps to maintain protein homeostasis in the ER (31). Activation of UPR in pulmonary endothelium increases levels of the tumor suppressor protein p53 (32), leading to inhibition of the inflammatory RhoA pathway, activation of Rac1, and ultimately enhanced vascular barrier function (33). p53 is crucial for maintaining vascular integrity, and its induction counteracts endothelial hyperpermeability and suppresses inflammatory NF-κB signaling (32, 34). Several therapeutic avenues that inhibit ER stress also exert protective effects in vascular endothelium by augmenting p53 and activating UPR branches; and inhibitors of ER stress emerge as therapeutic targets to prevent ARDS endothelial dysfunction. Despite different modes of action, heat shock protein 90 (HSP90) inhibitors (35–37) and growth hormone–releasing hormone (GHRH) antagonists (38, 39) induce p53 and trigger UPR, thus counteracting endothelial hyperpermeability (40). The promising results of preclinical studies suggest that UPR-modulating agents could provide therapeutic benefits for patients with ARDS by strengthening the vascular barrier.

The current understanding of the cellular stress response highlights the complexity of the underlying mechanisms involved in lung injury, emphasizing the need for a holistic approach that encompasses the intricate interplay between ECs, other cellular components, and the various factors they produce. Therefore, the development of treatment strategies necessitates a consideration of the vasculature’s role in the pathological process as well as the sequence of cell-cell interactions, since distinct factors come into play at different stages of the disease.

Fibroproliferative responses. ARDS pathobiology entails a transition from inflammation to fibrosis (41) characterized by increased collagen production (42) and excessive deposition of ECM components (43). Regardless of the causal agent, patients with ARDS face a heightened risk of developing lung fibrosis due to sustained damage to the lung parenchyma and vasculature (44–46). Endothelial dysfunction plays a crucial role in disturbing the delicate equilibrium between profibrotic and antifibrotic signals (Figure 1). In the bleomycin-induced injury model, the deletion of the endothelial transcription factor forkhead box F1 (FOXF1) leads to decreased expression of Ras-related protein (R-Ras), a vital regulator of EC barrier function and repair (47, 48). This process results in a fibrosis-conducive EC phenotype (46). Persistent EC activation causes the release of profibrotic factors (e.g., plasminogen activator inhibitor-1 and fibroblast-specific protein-1) and inflammatory mediators (CCL2, CCL3, CCL6, and CXCL2), creating an environment conducive to fibrosis development (49–53).

CLDs include COPD and ILDs such as idiopathic PF (IPF) and systemic sclerosis–associated ILD (SSc-ILD). Independent of disease entity, the presence of PH in CLDs (termed “group 3 pulmonary hypertension associated with lung diseases and/or hypoxia”; ref. 2) is associated with reduced exercise capacity, greater need for oxygen supplementation, decreased quality of life (54–56), and, in patients with severe PH, a worse prognosis (57, 58). Despite extensive research efforts, PH in CLDs continues to represent an unmet medical need.

Some clinicians posit that vascular remodeling and PH in CLDs are a consequence of hypoxia in areas of insufficient ventilation and diffusion (59). However, studies in several mouse models have shown that vascular remodeling can occur independently of hypoxia and precede the development of bleomycin-induced PF, Fra-2–induced SSc-ILD, and tobacco smoke–induced emphysema (60–63), suggesting that vascular alterations might play a more active role in the progression of underlying lung diseases than previously believed.

CLDs are age associated, and indeed, age-related changes, such as genomic instability, epigenetic alterations, and cellular senescence, have been described as affecting and contributing to the development of CLDs (64, 65). In addition to natural aging, cellular senescence can be induced by oxidative stress or smoking. Although senescent cells exhibit an arrested cell cycle, they remain metabolically active and can promote chronic inflammation via senescence-associated secretory phenotype (SASP), which is characterized by the release of inflammatory mediators and growth factors (66). It is conceivable that a so-called spillover of inflammatory factors from the lungs into circulation may affect the vascular system.

Vascular remodeling in interstitial lung disease

ILDs are characterized by progressive scarring and fibrosis of the lung, due to aberrant ECM deposition and proliferation of α-SMA–positive and –negative fibroblasts (67, 68). Although the progressive fibrotic nature of these diseases is a common denominator, the vasculature is also altered. In line with this, ILD lungs contain high numbers of severely remodeled vessels and exhibit mild to moderate PH (69).

While ECs were believed to be innocent bystanders, they have increasingly gained recognition as active drivers of ILDs (70) (Figure 1). Fibrotic lung regions show fewer ECs (71). Furthermore, in IPF there are fewer general capillary ECs capable of functioning as progenitors during homeostatic maintenance or repair after lung injury (72), suggesting that diminished regenerative properties of ECs contribute to persisting fibrosis (73).

Endothelial perturbations. The central role of ECs in the development and progression of vascular remodeling in lung fibrosis has been highlighted by a plethora of current studies. Endothelium-specific knockout of endothelin-1, a potent vasoconstrictor and profibrotic factor involved in PF (74) and PH (75), ameliorates vascular remodeling in the bleomycin mouse model, without affecting PF (76). In a TGF-β1–overexpressing rat model and in patients with PH and PF (PH-PF), EC dysfunction and vascular remodeling are associated with enhanced fibrosis (77). The contribution of ECs to pulmonary homeostasis and repair has been documented by EC-specific deletion of hepatocyte growth factor (HGF), which actively contributes to NOX4 activation in perivascular fibroblasts during bleomycin- or acid-induced lung injury in mice (78). Similarly, the presence of the endothelial transcription factor ETS-related gene (ERG) within the capillary endothelium is a prerequisite for tissue repair, and loss of ERG impairs the resolution of fibrosis following bleomycin-induced lung injury (79).

The endothelium not only contributes to tissue remodeling through endothelial-parenchymal crosstalk, but also serves as a recruitment site for circulating progenitor cells. For example, circulating endothelial colony-forming cells (ECFCs), which expand clonally and have the ability to form new blood vessels in vivo (80), have gained attention in vascular remodeling. ECFCs might contribute to IPF pathogenesis via higher prothrombotic potential (81), or through an apoptotic, senescent, and IL-8–producing phenotype that promotes neutrophil infiltration in vitro (82). Indeed, elevated levels of ECFCs with increased proliferative potential correlate with worse gas exchange in IPF (83) and diminished lung function in SSc-ILD (84). However, the role of ECFCs in PF has been questioned, as injection of ECFCs (from cord blood or IPF patient blood) failed to influence disease outcome in the bleomycin mouse model (85). Taking into account the lack of clear definition and ambiguities in the field of ECFCs (86), much more work is needed to understand their potential role in vascular remodeling in ILDs.

Endothelial-immune interface. Activated ECs express a variety of adhesion molecules (such as E-/P-selectin and ICAM-1/VCAM-1), which can also be found in the circulation of patients with PF/ILD and often correlate with poor lung function and outcome (70). These factors also crucially contribute to the recruitment and extravasation of inflammatory cells. In pulmonary arteries of fibrotic lungs, changes in T cells, macrophages, myeloid-derived suppressor cells (MDSCs), and mast cells have been reported and linked to vascular remodeling (87–89). Increased levels of lung MDSCs worsened vascular remodeling and PH without affecting parenchymal fibrosis in a mouse model of bleomycin-induced lung fibrosis (90, 91). Also, macrophages play a crucial role in PH development in the setting of PF. In the rat bleomycin-monocrotaline model, the inhibition of Slug (encoded by SNAI2), which is highly expressed in macrophages in PH-PF lungs, ameliorates PH (92). Furthermore, reducing macrophage infiltration via blockade of macrophage migration inhibitory factor (MIF) attenuated PH in mice following bleomycin administration (93, 94). In contrast to the increased macrophage numbers, natural killer T (NKT) cells were decreased in vessels of patients with PH-PF, accompanied by increased collagen (88). Restoration of NKT cells decreased vascular as well as parenchymal remodeling and PH in the bleomycin-induced fibrosis mouse model and reduced collagen deposition via activation of the STAT1/CXCL9/CXCR3 axis (88).

Chemokines and cytokines are important messengers in endothelial-inflammatory communication, although their effects can vary depending on the cell type involved. For instance, in the bleomycin mouse model, the knockout of CXCR2 in MDSCs ameliorated vascular remodeling and PH; however, EC-specific CXCR2 knockout worsened outcomes due to increased numbers of MDSCs (91). Additionally, IL-11 and its receptor IL-11Rα showed increased expression in pulmonary arterial SMCs (PASMCs) and ECs of IPF patients with PH versus those without PH (95). Exogenous administration of IL-11 in mice was sufficient to induce vascular remodeling, PH, and PF (95), highlighting the role of this cytokine in the development of PF-associated vascular remodeling.

Activated T cells represent another potent source of cytokines. Th2 inflammation, in particular, is a known driver of pulmonary remodeling, especially in systemic sclerosis (SSc). Many invaluable insights into the pathological processes involved in vascular remodeling have been gained from the SSc-ILD mouse model that is induced by Fra-2 overexpression. This model is characterized by progressive vascular remodeling, PF, chronic Th2 inflammation, and a concomitant decrease in regulatory T cells (Tregs) (62, 96, 97). Importantly, it was shown that Th2 cytokines, such as IL-4, predispose the ECs to exacerbated injury, leading to an aggravated disease phenotype following treatment with the antifibrotic drug pirfenidone in Fra-2–overexpressing mice, but not in bleomycin-treated mice (98). The clinical importance of restoring T cell homeostasis was also highlighted by treatments that improve vascular remodeling in this model, including the T cell costimulation blocker abatacept (99) and restoration of Tregs by either adoptive transfer or low-dose IL-2 treatment (100). Collectively, these studies emphasize the therapeutic potential of restoring EC-immune homeostasis. Furthermore, they provide valuable insights into the importance of understanding underlying disease pathomechanisms, particularly the specific inflammatory conditions that trigger preactivated endothelium and potentially lead to unfavorable outcomes.

Oxidative stress and ECM turnover. Inflammation is associated with oxidative stress that can induce cellular senescence, further promoting vascular remodeling. Mice lacking antioxidant extracellular superoxide dismutase 3 (SOD3) display worsened silica-induced PH-PF, with vascular remodeling in all pulmonary areas, while vascular remodeling in WT mice was limited to fibrotic areas (101). Many proteins involved in tissue homeostasis and repair, such as SOD3 or ERG, are decreased in older adults (79, 102). Taking into account our aging population and the higher prevalence of PF among older individuals, understanding these pathways becomes crucial in addressing the emerging health care challenge.

Oxidative stress is associated with DNA damage. Increased levels of the checkpoint inhibitors CHK1 and CHK2, members of the DNA damage control and repair system, have been reported in patients and animal models of PH-PF (103) (Table 2). CHK1/2 inhibition improves vascular remodeling and hemodynamics by preventing fibroblast-to-myofibroblast transition (103). The endothelial transcription factor sterol regulatory element–binding protein 2 (SREBP2), which is linked to oxidative stress response, contributes to vascular remodeling. SREBP2 is highly expressed in PF lungs and supports mesenchymal properties, thereby aggravating vascular remodeling (51). Also, dysregulation of protein translation via decreased eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) expression was documented in patients with PH-PF. Mutations of EIF2AK4 further worsened PH-PF in a rat bleomycin model, suggesting causative relations (104).

Table 2

Pathways associated with vascular remodeling in PF and ILD

The ECM and its associated proteins influence cellular behavior and contribute to vascular remodeling; one example is the matricellular CCN family of intercellular signaling proteins. In bleomycin-treated mice, CCN2, also known as connective tissue growth factor, was partially responsible for PH development (105), while CCN3 had beneficial effects on lung endothelial homeostasis, partially by antagonizing CCN2 expression (106). Galectin-3, a known profibrotic lectin, was also suggested to induce endothelial-mesenchymal transition in bleomycin-induced PF (107) and is currently the focus of a clinical trial in patients with IPF (108). Furthermore, hyaluronan, a major component of the ECM, and hyaluronan synthase 3 (HAS3) were upregulated in response to adenosine signaling and contributed to vascular remodeling in PF (109). Inhibition of this pathway using adenosine depletion or 4-methylumbelliferone, a blocker of HAS3 activity, ameliorated vascular manifestations in the Ada^–/– model of PH with combined pulmonary fibrosis and emphysema (CPFE) (109). 4-Methylumbelliferone also alleviated vascular pathologies in Fra-2 overexpression and graft-versus-host disease mouse models of SSc-ILD (110), further corroborating the important role of the ECM and/or hyaluronan production in the development of vascular remodeling in PF. Indeed, 4-methylumbelliferone is currently under investigation for the treatment of PH-ILD in a phase II clinical trial (ClinicalTrials.gov NCT05128929).

These studies underscore the central role of ECs in injury and repair processes, connecting immune cell homeostasis, cellular senescence, oxidative stress, and ECM deposition in the development of vascular remodeling and lung fibrosis (Table 2). In the future, our focus should shift toward better understanding the interplay between these processes and disease dynamics. Instead of seeking and treating a singular culprit, the objective should be to restore tissue homeostasis, thereby improving the overall disease phenotype. Furthermore, it has to be kept in mind that different ILD entities with diverse underlying pathomechanisms may require specific treatments, as pre-injured ECs could be further activated, thereby initiating detrimental rather than beneficial effects.

Vascular remodeling in COPD

COPD is the most common CLD and the third most common cause of death worldwide (111). It is characterized by the destruction of parenchyma, airspace enlargement, and airway remodeling with aberrant mucus production and hyperresponsiveness (112). In COPD, PH is typically mild to moderate; however, up to 4% of COPD patients present with severe PH but only mild to moderate airway obstruction (113, 114). Patients in this group are described as having the pulmonary vascular phenotype (115). Pulmonary vascular alterations in these patients include medial hypertrophy and intimal thickening, with the degree of remodeling depending on disease severity (116, 117). In COPD accompanied by severe PH, vascular remodeling is more morphologically similar to that seen in idiopathic pulmonary arterial hypertension (PAH) than to that noted in COPD with mild to moderate PH (117, 118). However, vascular remodeling can also be observed in explanted COPD lungs even without PH (116, 119).

The pathological mechanisms underlying the development of PH in COPD (PH-COPD) are still poorly understood. Early triggers may include endothelial dysfunction, especially in combination with cigarette smoke exposure, leading to inflammatory and oxidative stress. Hypoxia exposure additionally damages ECs, and leads to vasoconstriction and consequently compensatory remodeling (120, 121). It has also been postulated that progressive capillary loss leads to the simultaneous loss of terminal bronchioles and associated arteries (122–124).

The loss of endothelium is an early event in emphysema development, where changes in VEGF signaling promote cell apoptosis (125). Furthermore, isolated pulmonary arteries from COPD samples exhibit endothelial dysfunction (126, 127). Although advanced COPD does not associate with EC population shifts (neither in the macro- nor the microvasculature), EC gene expression profiles indicate an increase in the inflammatory signaling stress response and a decrease in vessel development (128). In an elastase-induced emphysema mouse model, disruption of the pulmonary endothelium promotes a pro-angiogenic state, and i.v. injection of healthy lung ECs reversed emphysema (129). Many factors released during EC activation and injury recruit and modulate immune cells, which might influence and further accelerate the tissue pathobiology.

Cellular senescence. One of the most important risk factors for COPD is old age. Age-related processes, including cellular senescence, indeed, crucially contribute to the pathomechanisms of COPD. For example, in patients with COPD, expression of phospholipase A₂ receptor 1 (PLA2R1) is increased and localized to alveolar epithelial type II cells, ECs, and PASMCs. In mice, overexpression of PLA2R1 induces EC senescence, lung emphysema, and PH (130). The senescence-associated mTOR pathway is activated in COPD lungs and drives EC senescence and emphysema (131). In addition, several microRNAs have been implicated in the regulation of cellular senescence or vascular remodeling in COPD (132–136) (Table 3). Exemplarily, microRNA-126 (miR-126), which has well-documented roles in lung regeneration and homeostasis, is downregulated in senescent ECs (137) and was recently linked to vascular remodeling in COPD (138) (Figure 1).

Table 3

Pathways associated with vascular remodeling in COPD

Oxidative stress. Independent of age, oxidative stress can induce cellular senescence. Increased oxidative stress in COPD can derive from structural and immune cells. Recent evidence has suggested a role for macrophage iNOS (NOS2) in mediating smoke-induced PH (139). iNOS, an enzyme involved in the macrophage inflammatory response and upregulated by hypoxia or proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), or interferon-γ (IFN-γ), plays a crucial role in the development of tobacco smoke–induced emphysema and PH in mice (61). However, specific deletion of iNOS in the bone marrow or macrophages protects against smoke-induced PH, but not emphysema (61, 139). Similarly, ROS-induced activation of the non-lysosomal cysteine protease calpain contributes to vascular but not parenchymal remodeling in COPD (140). Neuronal nitric oxide synthase 1 (NOS1) was recently revealed to be a direct target of miR-4640-5p, whose expression is markedly higher in PH-COPD lung tissue compared with healthy controls (136). NOXO1, a subunit of the non-phagocytic NADPH oxidase, is a source of superoxide, which drives emphysema and PH in cigarette smoke–exposed mice (141, 142). The expression of another NADPH subunit, NOX4, correlates with increased pulmonary vascular wall volume in COPD lungs (143), where it is speculated to promote ROS production and distal pulmonary vascular remodeling. Interestingly, high levels of the antioxidant SOD3 can also contribute to vascular remodeling in COPD, through increased levels of hydrogen peroxide (144). Cumulatively, these studies highlight the contribution of oxidative stress to vascular remodeling and shed light on its potential as a therapeutic target. Indeed, antioxidant treatment using MitoQ, which targets mitochondrial ROS production, restored endothelial barrier function and diminished activation of proinflammatory pathways in ECs (145).

Immune cell alterations. In the pulmonary arterial wall of patients with COPD, an increase in the number of CD45⁺ cells has been observed, along with a decrease in the number of circulating progenitor cells. These changes were associated with endothelial dysfunction and vessel remodeling (146). In the adventitial layer, total leukocytes increase, especially CD8⁺ T cells, albeit with no changes in neutrophil or macrophage numbers. Furthermore, the total number of leukocytes was associated with the degree of intimal thickening (147). Although the number of monocytes and macrophages in COPD vessels is maintained, these cells may still contribute to vascular remodeling in PH-COPD. In emphysema, the arginine methyltransferase PRMT7 promotes the extravasation of monocytes, resulting in tissue injury (148). Similar mechanisms may also damage the vascular wall and contribute to vascular remodeling. COPD lungs possess increased tertiary lymphoid structures, which are rich in B and T cells. As tertiary lymphoid structures have been linked with idiopathic PAH (149), it would be useful to determine their relevance in PH-COPD. In line with this, regulatory B cells (Bregs) were downregulated in the circulation of COPD patients, and their ability to produce IL-10 in response to cigarette smoke exposure was limited, contributing to the inflammatory milieu in COPD lungs (150). In addition, Bregs are involved in COPD vascular remodeling by influencing T cell differentiation (toward Th cells and away from Tregs) and PASMC proliferation (151).

PH-COPD is also associated with increased circulating cytokines including IL-6 (152), TNF-α (153), and the alarmin HMGB1 (154), all of which are strongly implicated in PH pathogenesis. Increased IL-6 plasma levels correlate with mean pulmonary arterial pressure (mPAP), further supporting the role of inflammation in the pathogenesis of PH-COPD (155). TNF-α is a potent activator of ECs, facilitating inflammatory cell recruitment. HMGB1 acts as a chemoattractant and induces the proliferation of PASMCs and ECs, via ERK/JNK and AP1 (153).

Vascular remodeling in COPD remains an enigma, and much work is still needed to delineate its active contribution to COPD development. Again, ECs appear to play a dominant role, as a multitude of factors contribute to their dysfunction, ultimately leading to vascular remodeling and emphysema (Table 3). Further investigations are warranted to comprehensively explore the impact of oxidative stress, cellular senescence, and the immune system, not only within the local vasculature and lungs but also on a systemic level.

Conclusions, future challenges, and opportunities

Despite the divergent effects of ILD and COPD on the lung parenchyma, with ILD associated with abnormal fibrosis and COPD characterized by tissue degradation, both diseases share the common complication of vascular remodeling, which worsens patient outcomes. Pulmonary vascular remodeling in PH-PF is particularly notable, marked by substantial collagen deposition, whereas in PH-COPD, it is comparatively less pronounced (116, 156, 157) (Figures 2 and 3). The diverse vascular alterations are reflected by different gene expression patterns and immune cell composition in pulmonary arteries isolated from these two entities (116, 157), indicating that targeted treatments for each disease may be necessary. Despite these differences, several pathways, such as oxidative stress and cellular senescence, seem to be shared in the vascular remodeling of ILDs and COPD (Figure 3). However, our understanding of common and diverse underlying pathomechanisms remains limited by a lack of comparative studies. Furthermore, mechanistic and functional studies often rely on animal models, which despite their advantages often do not fully recapitulate human disease (Table 4). Especially in complex diseases such as ILDs or COPD, characterized by diverse etiologies and/or endotypes, animal models have to be chosen with care depending on the underlying pathomechanism to fully exploit their translational potential.

Figure 2

Endothelium at the center of tissue maintenance and development of CLDs. The endothelium plays a key role in regulating vessel homeostasis by exerting a predominantly inhibitory effect on inflammation. Different stressors can activate ECs and induce loss of their barrier function, promoting leukocyte adhesion and transendothelial migration. Exacerbated EC dysfunction together with activation of inflammatory response and recruitment of leukocytes creates an inflammatory storm, leading to tissue destruction and subsequent remodeling. If not resolved, or if sustained tissue damage is too great, this process can lead to the onset of progressive fibrosis in the lung tissue. However, beyond acute EC damage, chronic EC dysfunction also emerges as an important player in CLD development. Vascular alterations — although to a different degree — are commonly found in CLDs, irrespective of their etiology, and can lead to the development of PH. Importantly, vessels contribute to the regulation of immune cell homeostasis and actively participate in the propagation of tissue damage, as seen in COPD, or remodeling, as occurs in PH-PF.

Figure 3

Vascular remodeling in the lungs of PH-PF and PH-COPD patients. Pulmonary arteries of patients with PH-PF present with more pronounced intimal and medial remodeling, reflected as thickness changes that vary with vessel size. The vessels of patients with PH-PF also show increased collagen deposition as compared with those from patients with PH-COPD. The two conditions are further distinguished by diversity in corresponding immune cell profiles (116, 156, 157). Differential gene expression and regulated pathways, including those related to the ECM and retinol metabolism, underscore the differences between PH-PF and PH-COPD (116). However, several general mechanisms, such as cellular senescence, oxidative stress, and disturbed EC homeostasis, seem to be shared in the vascular remodeling processes of patients with PH-PF and PH-COPD.

Table 4

Animal models of CLDs

Substantial progress has been made in characterizing pathomechanisms driving vascular remodeling in various CLDs. However, it is important to acknowledge that our current understanding of the disturbed EC function and immune homeostasis remains limited and represents only the tip of the iceberg. Delineating interconnections and crosstalk between the endothelium, surrounding structural cells, and the immune system will help in understanding disease pathobiology. Here, single-cell omics approaches can give excellent insights into intercellular communication and interaction pathways. In addition, artificial intelligence and machine learning will provide unknown opportunities with respect to image analysis and multi-omics data interpretation. However, confirmatory approaches and in vivo studies will be needed to validate the postulated interdependencies. The next big challenge will be to target cell type–specific alterations delineated by these technologies. Nevertheless, a better understanding of the molecular and cellular processes underlying vascular pathology could pave the way for the development of targeted interventions that can effectively restore tissue homeostasis and improve clinical outcomes in a disease-specific manner.

Targeting the vasculature in ARDS

Similarities in the mechanism of vascular remodeling between PAH and ARDS have led to the investigation of PAH drugs as potential treatments for ARDS (Table 1). However, despite promising results from animal studies, these positive outcomes have not yet translated into clinical benefits for patients. Inhaled pulmonary vasodilators, despite their physiological advantages, such as improving ventilation/perfusion mismatch and reducing hypoxia-induced vasoconstriction and PH, did not decrease overall mortality (158, 159). Interestingly, the effectiveness of interventions appears to be influenced by the timing of their implementation. For example, the use of epoprostenol, a synthetic prostacyclin, was found to worsen oxygenation when administered to ARDS patients with pneumonia. However, when administered during secondary ARDS, epoprostenol improved oxygenation (160).

Numerous other pharmacological interventions have been tested in ARDS patients. However, none provided notable clinical benefits. As selective pharmacological interventions have not yielded the anticipated therapeutic benefits, it may be necessary to shift toward an approach that takes into account the disease dynamics and multitude of factors contributing to the syndrome’s mechanisms.

Targeting the vasculature in ILDs

Several clinical trials assessing the efficacy of endothelin receptor blockers, such as ambrisentan, bosentan, and macitentan, in treating patients with IPF did not show clinical benefits (Table 1). Notably, the trial involving ambrisentan had to be prematurely terminated because of safety concerns (161–164). Similarly, a clinical study with riociguat in idiopathic interstitial pneumonia–associated PH was discontinued due to an increased risk of hospitalization and death (165). Also, sildenafil did not meet the primary endpoint of improving the 6-minute walk distance (6MWD) in patients with IPF, although small improvements in secondary endpoints, including the degree of dyspnea and quality of life, were observed (166). Trials investigating sildenafil in combination with antifibrotic treatment such as nintedanib (167) or pirfenidone (168) did not provide added clinical benefit for ILD patients.

However, the recent INCREASE trial provided compelling evidence supporting the use of inhaled treprostinil in the treatment of PH in ILD (PH-ILD). In comparison with patients receiving treatment solely for the underlying lung disease, the addition of treprostinil improved 6MWD and N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and decreased the risk of clinical worsening (55). Furthermore, post hoc analysis showed that treprostinil inhalation had a positive influence on forced vital capacity (169).

Targeting the vasculature in COPD

In the context of PH-COPD, the administration of PAH-specific therapy also has shown limited benefits (Table 1). The available evidence from clinical studies with bosentan remains inconclusive. On one hand, administration of bosentan in COPD patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grading stages III–IV (severe and very severe) did not lead to an improvement in the 6MWD and worsened hypoxemia due to ventilation/perfusion mismatch (170). On the other hand, a small preliminary study involving patients with PH-COPD reported positive outcomes, including improvements in mPAP, pulmonary vascular resistance (PVR), and 6MWD (171). Similarly, the investigation of sildenafil in PH-COPD has yielded mixed results. One clinical trial showed that sildenafil treatment did not improve 6MWD or oxygenation (172). However, another study found that sildenafil administration decreased PVR, and improved the body mass, airflow obstruction, dyspnea, exercise capacity (BODE) index and diffusion capacity of the lung for carbon monoxide (DLCO) (173). Currently, it is proposed that patients with PH-COPD who present with pulmonary vascular phenotype might benefit from vasoactive medications (115).

Future treatment options and considerations

Despite the numerous clinical trials conducted in PH related to CLD, the practical impact on patient outcomes remains limited (Table 1). A meta-analysis of studies investigating PAH-specific therapies in PH occurring in CLDs has concluded that there is insufficient evidence to justify the routine use of PAH-specific therapy in the context of CLD (134). It is evident that vasodilators offer limited clinical benefits, highlighting the need for a more holistic approach that takes into account the underlying pathomechanisms of lung disease. For instance, inhaled treprostinil is effective, and FDA approved, for the treatment of PH-ILD, but lacks sufficient evidence for use in PH-COPD, indicating that the underlying lung disease can lead to different patient outcomes. The positive effects of inhaled treprostinil in ILD might result from direct improvements in the vascular compartment that occur as a consequence of inhibition of parenchymal fibroblast proliferation or from modulation of the local inflammatory milleu (174, 175). Targeting proliferative mechanisms in the vasculature and parenchyma appears to benefit patients with PH-ILD; however, this strategy might be deleterious in PH-COPD, in which the lung parenchyma is mostly destroyed. Here, restoration of regenerative pathways, rather than antiproliferative approaches, will be needed to successfully treat PH-COPD without worsening the underlying disease.

Mounting evidence supports the crucial role of the vasculature in acute lung disease and CLDs. Notably, CLDs are diseases of the older population in which dysfunctional endothelium plays a key role. Also, the mortality of ARDS patients increases with age, possibly as a result of so-called “exhausted” ECs. Therefore, addressing EC senescence and dysfunction becomes a vital step in reestablishing tissue homeostasis. Since immune cells and EC function are closely interconnected, the development of therapeutic strategies aimed at supporting endothelial integrity and function must also address the inflammatory aspects.

Although our knowledge is expanding, a holistic view of acute and chronic lung diseases has been confounded by a compartmentalized view of these diseases. Past oversights regarding the pathological contribution of the vasculature in the setting of ILDs or COPD may have hindered the development of successful treatment strategies. By bringing together all the results gained in recent years, it becomes clear that lung diseases cannot be defined purely as airway disease or interstitial disease, as pathobiology involves the entire lung. In addition, the participation of the systemic circulation and the bone marrow as supply lines for recruited inflammatory and immune cells should not be ignored. Consideration for the vasculature in ARDS and CLDs will add additional complexity but also expand therapeutic possibilities in targeting intravascular inflammation and the endothelial–immune cell interaction. It is also plausible that rebalancing oxidative stress and senescence might prolong the longevity of ECs, thus preventing the development of CLDs. Furthermore, gaining a comprehensive understanding of diverse EC phenotypes, and characterizing the trajectories of disease progressions, will be instrumental in delineating the pivotal transition of ECs from a reparative role to pathobiological involvement. It is still unclear whether it will be possible to restore EC homeostasis; however, given the key role of ECs in acute and chronic lung diseases, this lofty goal is definitely worth seeking. We believe that changing our compartment-oriented view of lung diseases is a prerequisite for the successful development of therapies that restore perfusion and gas exchange and reestablish immune, endothelial, and tissue homeostasis to improve lung function and, ultimately, the survival of patients with lung diseases.

IB and AB made equal contributions to the literature search and manuscript preparation. IB additionally performed final proofreading, editing, and adjustments, which is why she is listed first.

GK is a speaker for the Austrian Science Fund (FWF) DOC 129 doc.funds program of Immune Modulation in Respiratory Diseases (RESPIMMUN). LMM is a holder of an FWF KLI 844 Programm Klinische Forschung (KLIF) grant from FWF.

Address correspondence to: Grazyna Kwapiszewska, Ludwig Boltzmann Institute for Lung Vascular Research c/o ZMF Neue Stiftingtalstraße 6/VI, 8010 Graz, Austria. Phone: 0043.0.316.385.72918; Email: Grazyna.Kwapiszewska@lvr.lbg.ac.at.

Conflict of interest: NV is a cofounder of and shareholder in Artin BioScience Inc.

Copyright: © 2023, Borek et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2023;133(16):e170502. https://doi.org/10.1172/JCI170502.

1. Huertas A, et al. Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases: highlights from basic research to therapy. Eur Respir J. 2018;51(4):1700745.
   View this article via: CrossRef PubMed Google Scholar
2. Humbert M, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618–3731.
   View this article via: CrossRef PubMed Google Scholar
3. Tuder RM. Pulmonary vascular remodeling in pulmonary hypertension. Cell Tissue Res. 2017;367(3):643–649.
   View this article via: CrossRef PubMed Google Scholar
4. Ranieri VM, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–2533.
   View this article via: PubMed Google Scholar
5. Bellani G, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800.
   View this article via: CrossRef PubMed Google Scholar
6. Tomashefski JF, et al. The pulmonary vascular lesions of the adult respiratory distress syndrome. Am J Pathol. 1983;112(1):112–126.
   View this article via: PubMed Google Scholar
7. Snow RL, et al. Pulmonary vascular remodeling in adult respiratory distress syndrome. Am Rev Respir Dis. 1982;126(5):887–892.
   View this article via: PubMed Google Scholar
8. Karmouty-Quintana H, et al. Emerging mechanisms of pulmonary vasoconstriction in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) and potential therapeutic targets. Int J Mol Sci. 2020;21(21):1–21.
   View this article via: CrossRef PubMed Google Scholar
9. Owen A, et al. Mechanisms of post-critical illness cardiovascular disease. Front Cardiovasc Med. 2022;9:1–24.
   View this article via: CrossRef PubMed Google Scholar
10. Jadaun PK, Chatterjee S. COVID-19 and dys-regulation of pulmonary endothelium: implications for vascular remodeling. Cytokine Growth Factor Rev. 2022;63:69–77.
    View this article via: CrossRef PubMed Google Scholar
11. Oliveira SDS, et al. Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-β-driven pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol. 2017;312(5):L760–L771.
    View this article via: CrossRef PubMed Google Scholar
12. D’Agnillo FD, et al. Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19. Sci Transl Med. 2021;13(620):eabj7790.
    View this article via: CrossRef PubMed Google Scholar
13. Tzotzos SJ, et al. Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey. Crit Care. 2020;24(1):516.
    View this article via: CrossRef PubMed Google Scholar
14. Ackermann M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–128.
    View this article via: CrossRef PubMed Google Scholar
15. Urata R, et al. Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction. Sci Rep. 2022;12(1):1–9.
    View this article via: CrossRef PubMed Google Scholar
16. Pelisek J, et al. Vascular dysfunction in COVID-19 patients: update on SARS-CoV-2 infection of endothelial cells and the role of long non-coding RNAs. Clin Sci (Lond). 2022;136(21):1571–1590.
    View this article via: CrossRef PubMed Google Scholar
17. Halawa S, et al. Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective. Nat Rev Cardiol. 2022;19(5):314–331.
    View this article via: CrossRef PubMed Google Scholar
18. Zhang L, et al. Single-cell transcriptomic profiling of lung endothelial cells identifies dynamic inflammatory and regenerative subpopulations. JCI Insight. 2022;7(11):e158079.
    View this article via: JCI Insight CrossRef PubMed Google Scholar
19. Niethamer TK, et al. Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury. Elife. 2020;9:e53072.
    View this article via: CrossRef PubMed Google Scholar
20. Orfanos SE, et al. Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med. 2004;30(9):1702–1714.
    View this article via: CrossRef PubMed Google Scholar
21. Birnhuber A, et al. Between inflammation and thrombosis: endothelial cells in COVID-19. Eur Respir J. 2021;58(3):2100377.
    View this article via: CrossRef PubMed Google Scholar
22. Chen C-M, et al. Antiplatelet therapy for acute respiratory distress syndrome. Biomedicines. 2020;8(7):2030.
    View this article via: CrossRef PubMed Google Scholar
23. Frantzeskaki F, et al. Immunothrombosis in acute respiratory distress syndrome: cross talks between inflammation and coagulation. Respiration. 2017;93(3):212–225.
    View this article via: CrossRef PubMed Google Scholar
24. Liu KD, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med. 2008;178(6):618–623.
    View this article via: CrossRef PubMed Google Scholar
25. Allingstrup M, et al. Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2016;2:CD005370.
    View this article via: PubMed Google Scholar
26. Aulakh GK. Neutrophils in the lung: “the first responders. ” Cell Tissue Res. 2018;371(3):577–588.
    View this article via: CrossRef PubMed Google Scholar
27. Yang SC, et al. Understanding the role of neutrophils in acute respiratory distress syndrome. Biomed J. 2021;44(4):439–446.
    View this article via: CrossRef PubMed Google Scholar
28. Maniatis NA, et al. Caveolins and lung function. Adv Exp Med Biol. 2012;729:157–179.
    View this article via: CrossRef PubMed Google Scholar
29. Razani B, et al. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem. 2001;276(41):38121–38138.
    View this article via: CrossRef PubMed Google Scholar
30. Zhao Y, et al. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest. 2009;119(7):2009–2018.
    View this article via: JCI CrossRef PubMed Google Scholar
31. Hetz C, et al. Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015;17(7):829–838.
    View this article via: CrossRef PubMed Google Scholar
32. Akhter MS, et al. Unfolded protein response regulates P53 expression in the pulmonary endothelium. J Biochem Mol Toxicol. 2019;33(10):1–5.
    View this article via: CrossRef PubMed Google Scholar
33. Barabutis N, et al. Wild-type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition. J Cell Mol Med. 2018;22(3):1792–1804.
    View this article via: CrossRef PubMed Google Scholar
34. Barabutis N, et al. p53 protects against LPS-induced lung endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2015;308(8):776–L787.
    View this article via: CrossRef PubMed Google Scholar
35. Kubra K, et al. Luminespib counteracts the Kifunensine-induced lung endothelial barrier dysfunction. Curr Res Toxicol. 2020;1:111–115.
    View this article via: CrossRef PubMed Google Scholar
36. Kubra K, et al. Hsp90 inhibitors induce the unfolded protein response in bovine and mice lung cells. Cell Signal. 2020;67:109500.
    View this article via: CrossRef PubMed Google Scholar
37. Chatterjee A, et al. Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis. Am J Respir Crit Care Med. 2007;176(7):667–675.
    View this article via: CrossRef PubMed Google Scholar
38. Akhter MS, et al. Involvement of the unfolded protein response in the protective effects of growth hormone releasing hormone antagonists in the lungs. J Cell Commun Signal. 2021;15(1):125–129.
    View this article via: CrossRef PubMed Google Scholar
39. Uddin MA, et al. GHRH antagonists support lung endothelial barrier function. Tissue Barriers. 2019;7(4):e1669989.
    View this article via: CrossRef PubMed Google Scholar
40. Barabutis N. Unfolded protein response: a regulator of the endothelial barrier. Endocr Metab Sci. 2021;3:100092.
    View this article via: CrossRef PubMed Google Scholar
41. Kamp JC, et al. Time-dependent molecular motifs of pulmonary fibrogenesis in COVID-19. Int J Mol Sci. 2022;23(3):1–16.
    View this article via: CrossRef PubMed Google Scholar
42. Zapol WM, et al. Pulmonary fibrosis in severe acute respiratory failure. Am Rev Respir Dis. 1979;119(4):547–554.
    View this article via: PubMed Google Scholar
43. Ichikado K, et al. Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases. Radiology. 2005;238(1):321–329.
    View this article via: CrossRef PubMed Google Scholar
44. Burnham EL, et al. The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance. Eur Respir J. 2014;43(1):276–285.
    View this article via: CrossRef PubMed Google Scholar
45. Marshall R, et al. The acute respiratory distress syndrome: fibrosis in the fast lane. Thorax. 1998;53(10):815–817.
    View this article via: CrossRef PubMed Google Scholar
46. Michalski JE, et al. From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic? Transl Res. 2022;241:13–24.
    View this article via: CrossRef PubMed Google Scholar
47. Sawada J, et al. Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels. Cancer Cell. 2012;22(2):235–249.
    View this article via: CrossRef PubMed Google Scholar
48. Li F, et al. R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature. Nat Commun. 2017;8(1):1720.
    View this article via: CrossRef PubMed Google Scholar
49. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117(3):524–529.
    View this article via: JCI CrossRef PubMed Google Scholar
50. Zhao W, et al. Injured endothelial cell: a risk factor for pulmonary fibrosis. Int J Mol Sci. 2023;24(10):8749.
    View this article via: CrossRef PubMed Google Scholar
51. Martin M, et al. Role of endothelial cells in pulmonary fibrosis via SREBP2 activation. JCI Insight. 2021;6(22):e125635.
    View this article via: JCI Insight CrossRef PubMed Google Scholar
52. Bian F, et al. Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling. Nat Commun. 2023;14(1):2560.
    View this article via: CrossRef PubMed Google Scholar
53. Leach HG, et al. Endothelial cells recruit macrophages and contribute to a fibrotic milieu in bleomycin lung injury. Am J Respir Cell Mol Biol. 2013;49(6):1093–1101.
    View this article via: CrossRef PubMed Google Scholar
54. Nathan SD, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019;53(1):1801914.
    View this article via: CrossRef PubMed Google Scholar
55. Waxman A, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med. 2021;384(4):325–334.
    View this article via: CrossRef PubMed Google Scholar
56. Seeger W, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62:D109–D116.
    View this article via: CrossRef PubMed Google Scholar
57. Alkhanfar D, et al. Severe pulmonary hypertension associated with lung disease is characterised by a loss of small pulmonary vessels on quantitative computed tomography. ERJ Open Res. 2022;8(2):00503-2021.
    View this article via: CrossRef PubMed Google Scholar
58. Chaouat A, et al. Severe pulmonary hypertension associated with chronic obstructive pulmonary disease: a prospective French multicenter cohort. J Heart Lung Transplant. 2005;172(9):189–1018.
    View this article via: PubMed Google Scholar
59. Ruggiero RM, et al. Pulmonary hypertension in parenchymal lung disease. Heart Fail Clin. 2012;8:461–474.
    View this article via: CrossRef PubMed Google Scholar
60. Darwiche T, et al. Alterations in cardiovascular function in an experimental model of lung fibrosis and pulmonary hypertension. Exp Physiol. 2019;104(4):568–579.
    View this article via: CrossRef PubMed Google Scholar
61. Seimetz M, et al. Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell. 2011;147(2):293–305.
    View this article via: CrossRef PubMed Google Scholar
62. Biasin V, et al. Meprin β, a novel mediator of vascular remodelling underlying pulmonary hypertension. J Pathol. 2014;1(1):7–17.
    View this article via: CrossRef PubMed Google Scholar
63. Birnhuber A, et al. Transcription factor Fra-2 and its emerging role in matrix deposition, proliferation and inflammation in chronic lung diseases. Cell Signal. 2019;64:109408.
    View this article via: CrossRef PubMed Google Scholar
64. Cho SJ, Stout-Delgado HW. Aging and lung disease. Annu Rev Physiol. 2021;82:433–459.
    View this article via: CrossRef PubMed Google Scholar
65. Barnes PJ, et al. Cellular senescence as a mechanism and target in chronic lung diseases. Am J Respir Crit Care Med. 2019;200(5):556–564.
    View this article via: CrossRef PubMed Google Scholar
66. Coppe J-P, et al. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.
    View this article via: CrossRef PubMed Google Scholar
67. Biasin V, et al. PDGFRα and αSMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2020;318(4):L684–L697.
    View this article via: CrossRef Google Scholar
68. Samarelli AV, et al. Fibrotic idiopathic interstitial lung disease: the molecular and cellular key players. Int J Mol Sci. 2021;22(16):8952.
    View this article via: CrossRef PubMed Google Scholar
69. Dotan Y, et al. Pulmonary vasculopathy in explanted lungs from patients with interstitial lung disease undergoing lung transplantation. BMJ Open Respir Res. 2020;7(1):e000532.
    View this article via: CrossRef PubMed Google Scholar
70. Fließer E, et al. The endothelium in lung fibrosis — a core signaling hub in disease pathogenesis? Am J Physiol Cell Physiol. 2023;325(1):C2–C16.
    View this article via: CrossRef PubMed Google Scholar
71. Farkas L, et al. Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors. Am J Respir Cell Mol Biol. 2011;45(1):1–15.
    View this article via: CrossRef PubMed Google Scholar
72. Gillich A, et al. Capillary cell-type specialization in the alveolus. Nature. 2020;586(7831):785–789.
    View this article via: CrossRef PubMed Google Scholar
73. Adams TS, et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv. 2020;6(28):eaba1983.
    View this article via: CrossRef PubMed Google Scholar
74. Vizza CD, et al. Pulmonary hypertension in patients with COPD: results from the comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA). Chest. 2021;160(2):678–689.
    View this article via: CrossRef PubMed Google Scholar
75. Chester AH, Yacoub MH. The role of endothelin-1 in pulmonary arterial hypertension. Glob Cardiol Sci Pract. 2014;2014(2):29–78.
    View this article via: CrossRef PubMed Google Scholar
76. Hartopo AB, et al. Endothelial-derived endothelin-1 promotes pulmonary vascular remodeling in bleomycin-induced pulmonary fibrosis. Physiol Res. 2018;67(suppl 1):S185–S197.
    View this article via: CrossRef PubMed Google Scholar
77. Yanagihara T, et al. Vascular-parenchymal cross-talk promotes lung fibrosis through BMPR2 signaling. Am J Respir Crit Care Med. 2023;207(11):1498–1514.
    View this article via: CrossRef PubMed Google Scholar
78. Cao Z, et al. Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. Sci Transl Med. 2017;9(405):1–15.
    View this article via: CrossRef PubMed Google Scholar
79. Caporarello N, et al. Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis. Nat Commun. 2022;13(1):1–19.
    View this article via: CrossRef PubMed Google Scholar
80. Melero-Martin JM. Human endothelial colony-forming cells. Cold Spring Harb Perspect Med. 2022;12(12):a041156.
    View this article via: PubMed Google Scholar
81. Billoir P, et al. Endothelial colony-forming cells from idiopathic pulmonary fibrosis patients have a high procoagulant potential. Stem Cell Rev Rep. 2021;17(2):694–699.
    View this article via: CrossRef PubMed Google Scholar
82. Blandinières A, et al. Interleukin-8 release by endothelial colony-forming cells isolated from idiopathic pulmonary fibrosis patients might contribute to their pathogenicity. Angiogenesis. 2019;22(2):325–339.
    View this article via: CrossRef PubMed Google Scholar
83. Smadja DM, et al. Imbalance of circulating endothelial cells and progenitors in idiopathic pulmonary fibrosis. Angiogenesis. 2013;16(1):147–157.
    View this article via: CrossRef PubMed Google Scholar
84. Benyamine A, et al. Increased serum levels of fractalkine and mobilisation of CD34⁺CD45^- endothelial progenitor cells in systemic sclerosis. Arthritis Res Ther. 2017;19(1):1–11.
    View this article via: CrossRef PubMed Google Scholar
85. Blandinières A, et al. Endothelial colony-forming cells do not participate to fibrogenesis in a bleomycin-induced pulmonary fibrosis model in nude mice. Stem Cell Rev Rep. 2018;14(6):812–822.
    View this article via: CrossRef PubMed Google Scholar
86. Robertson JO, et al. Pathological roles for endothelial colony-forming cells in neonatal and adult lung disease. Am J Respir Cell Mol Biol. 2023;68(1):13–22.
    View this article via: CrossRef PubMed Google Scholar
87. Bryant AJ, et al. Myeloid-derived suppressor cells are necessary for development of pulmonary hypertension. Am J Respir Cell Mol Biol. 2018;58(2):170–180.
    View this article via: CrossRef PubMed Google Scholar
88. Jandl K, et al. Impairment of the NKT-STAT1-CXCL9 axis contributes to vessel fibrosis in pulmonary hypertension caused by lung fibrosis. Am J Respir Crit Care Med. 2022;206(8):981–998.
    View this article via: CrossRef PubMed Google Scholar
89. Kosanovic D, et al. Chymase: a multifunctional player in PH associated with lung fibrosis. Eur Respir J. 2015;46(4):1084–1094.
    View this article via: CrossRef PubMed Google Scholar
90. Fu C, et al. Emergency myelopoiesis contributes to immune cell exhaustion and pulmonary vascular remodelling. Br J Pharmacol. 2021;178(1):187–202.
    View this article via: CrossRef PubMed Google Scholar
91. Oliveira AC, et al. Chemokine signaling axis between endothelial and myeloid cells regulates development of pulmonary hypertension associated with pulmonary fibrosis and hypoxia. Am J Physiol Lung Cell Mol Physiol. 2019;317(4):L434–L444.
    View this article via: CrossRef PubMed Google Scholar
92. Ruffenach G, et al. Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis. EMBO Mol Med. 2019;11(9):1–19.
    View this article via: CrossRef PubMed Google Scholar
93. Luo Y, et al. Inhibition of macrophage migration inhibitory factor (MIF) as a therapeutic target in bleomycin-induced pulmonary fibrosis rats. Am J Physiol Lung Cell Mol Physiol. 2021;321(1):L6–L16.
    View this article via: CrossRef PubMed Google Scholar
94. Günther S, et al. Macrophage migration inhibitory factor (MIF) inhibition in a murine model of bleomycin-induced pulmonary fibrosis. Int J Mol Sci. 2018;19(12):1–14.
    View this article via: CrossRef PubMed Google Scholar
95. Milara J, et al. IL-11 system participates in pulmonary artery remodeling and hypertension in pulmonary fibrosis. Respir Res. 2022;23(1):1–18.
    View this article via: CrossRef PubMed Google Scholar
96. Eferl R, et al. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc Natl Acad Sci U S A. 2008;105(30):10525–10530.
    View this article via: CrossRef PubMed Google Scholar
97. Gungl A, et al. Fra2 overexpression in mice leads to non-allergic asthma development in an IL-13 dependent manner. Front Immunol. 2018;9:2018.
    View this article via: CrossRef PubMed Google Scholar
98. Birnhuber A, et al. Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of systemic sclerosis-associated interstitial lung disease. Eur Respir J. 2022;60(4):2102347.
    View this article via: CrossRef PubMed Google Scholar
99. Boleto G, et al. T-cell costimulation blockade is effective in experimental digestive and lung tissue fibrosis. Arthritis Res Ther. 2018;20(1):1–12.
    View this article via: CrossRef PubMed Google Scholar
100. Frantz C, et al. Driving role of interleukin-2-related regulatory CD4+ T cell deficiency in the development of lung fibrosis and vascular remodeling in a mouse model of systemic sclerosis. Arthritis Rheumatol. 2022;74(8):1387–1398.
     View this article via: CrossRef PubMed Google Scholar
101. Zelko IN, et al. Role of SOD3 in silica-related lung fibrosis and pulmonary vascular remodeling. Respir Res. 2018;19(1):1–14.
     View this article via: CrossRef PubMed Google Scholar
102. Abouhashem AS, et al. Is low alveolar type II cell SOD3 in the lungs of elderly linked to the observed severity of COVID-19? Antioxid Redox Signal. 2020;33(2):59–65.
     View this article via: CrossRef PubMed Google Scholar
103. Wu WH, et al. Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension. Thorax. 2022;77(3):247–258.
     View this article via: CrossRef PubMed Google Scholar
104. Santos-Ribeiro D, et al. Disruption of GCN2 pathway aggravates vascular and parenchymal remodeling during pulmonary fibrosis. Am J Respir Cell Mol Biol. 2023;68(3):326–338.
     View this article via: CrossRef PubMed Google Scholar
105. Pi L, et al. Vascular endothelial cell-specific connective tissue growth factor (CTGF) is necessary for development of chronic hypoxia-induced pulmonary hypertension. Front Physiol. 2018;9:1–13.
     View this article via: CrossRef PubMed Google Scholar
106. Betageri KR, et al. The matricellular protein CCN3 supports lung endothelial homeostasis and function. Am J Physiol Lung Cell Mol Physiol. 2023;324(2):L154–L168.
     View this article via: CrossRef PubMed Google Scholar
107. Jia W, et al. Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis. Cell Death Dis. 2021;12(4):327.
     View this article via: CrossRef PubMed Google Scholar
108. Hirani N, et al. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2021;57(5):1–13.
     View this article via: CrossRef PubMed Google Scholar
109. Collum SD, et al. Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema. Dis Model Mech. 2019;12(5):dmm038711.
     View this article via: CrossRef PubMed Google Scholar
110. Zhang Y, et al. Recombinant adenosine deaminase ameliorates inflammation, vascular disease, and fibrosis in preclinical models of systemic sclerosis. Arthritis Rheumatol. 2020;72(8):1385–1395.
     View this article via: CrossRef PubMed Google Scholar
111. Agustí A, et al. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Am J Respir Crit Care Med. 2023;61(4):2300239.
     View this article via: PubMed Google Scholar
112. Christenson SA, et al. Chronic obstructive pulmonary disease. Lancet. 2022;399(10342):2227–2242.
     View this article via: CrossRef PubMed Google Scholar
113. Thabut G, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest. 2005;127(5):1531–1536.
     View this article via: CrossRef PubMed Google Scholar
114. Dauriat G, et al. Severe pulmonary hypertension associated with chronic obstructive pulmonary disease: a prospective French multicenter cohort. J Heart Lung Transplant. 2021;40(9):1009–1018.
     View this article via: CrossRef PubMed Google Scholar
115. Kovacs G, et al. Pulmonary vascular involvement in chronic obstructive pulmonary disease. Is there a pulmonary vascular phenotype? Am J Respir Crit Care Med. 2018;198(8):1000–1011.
     View this article via: CrossRef PubMed Google Scholar
116. Hoffmann J, et al. Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension. Am J Respir Crit Care Med. 2014;190(1):98–111.
     View this article via: CrossRef PubMed Google Scholar
117. Bunel V, et al. Pulmonary arterial histologic lesions in patients with COPD with severe pulmonary hypertension. Chest. 2019;156(1):33–44.
     View this article via: CrossRef PubMed Google Scholar
118. Carlsen J, et al. Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease. J Heart Lung Transplant. 2013;32(3):347–354.
     View this article via: CrossRef PubMed Google Scholar
119. Demirag F, et al. Pulmonary vascular alterations in explanted lung after transplantation. Pol J Pathol. 2021;72(2):130–139.
     View this article via: PubMed Google Scholar
120. Blanco I, et al. Updated perspectives on pulmonary hypertension in COPD. Int J Chron Obstruct Pulmon Dis. 2020;15:1315–1324.
     View this article via: CrossRef PubMed Google Scholar
121. Gredic M, et al. Pulmonary hypertension in chronic obstructive pulmonary disease. Br J Pharmacol. 2021;178(1):132–151.
     View this article via: CrossRef PubMed Google Scholar
122. Washko GR, et al. Arterial vascular pruning, right ventricular size, and clinical outcomes in chronic obstructive pulmonary disease. A longitudinal observational study. Am J Respir Crit Care Med. 2019;200(4):454–461.
     View this article via: CrossRef PubMed Google Scholar
123. Rahaghi FN, et al. Pulmonary vascular density: comparison of findings on computed tomography imaging with histology. Eur Respir J. 2019;54(2):1900370.
     View this article via: CrossRef Google Scholar
124. Li R, et al. Can CT-based arterial and venous morphological markers of chronic obstructive pulmonary disease explain pulmonary vascular remodeling. [published online May 27, 2023]? Acad Radiol. doi:10.1016/j.acra.2023.04.026.
     View this article via: PubMed Google Scholar
125. Kasahara Y, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest. 2000;106(11):1311–1319.
     View this article via: JCI CrossRef PubMed Google Scholar
126. Peinado CI, et al. Endothelial dysfunction in pulmonary arteries of patients with mild COPD. Am J Physiol. 1998;274(6):L908–L913.
     View this article via: PubMed Google Scholar
127. Ding-Xuan AT, et al. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med. 1991;324(22):1539–1547.
     View this article via: CrossRef PubMed Google Scholar
128. Sauler M, et al. Characterization of the COPD alveolar niche using single-cell RNA sequencing. Nat Commun. 2022;13(1):494.
     View this article via: CrossRef PubMed Google Scholar
129. Hisata S, et al. Reversal of emphysema by restoration of pulmonary endothelial cells. J Exp Med. 2021;218(8):e20200938.
     View this article via: CrossRef PubMed Google Scholar
130. Beaulieu D, et al. Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease. Eur Respir J. 2021;58(2):1–15.
     View this article via: CrossRef PubMed Google Scholar
131. Houssaini A, et al. mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight. 2018;3(3):e93203.
     View this article via: JCI Insight CrossRef PubMed Google Scholar
132. Musri MM, et al. MicroRNA dysregulation in pulmonary arteries from chronic obstructive pulmonary disease. Relationships with vascular remodeling. Am J Respir Cell Mol Biol. 2018;59(4):490–499.
     View this article via: CrossRef PubMed Google Scholar
133. Zhou S, et al. Circular RNA hsa_circ_0016070 is associated with pulmonary arterial hypertension by promoting PASMC Proliferation. Mol Ther Nucleic Acid. 2019;18:275–284.
     View this article via: CrossRef PubMed Google Scholar
134. Li T, et al. MicroRNA miR‑627‑5p restrains pulmonary artery smooth muscle cell dysfunction by targeting MAP 2 K4 and PI3K/AKT signaling. Genes Environ. 2022;44(1):23.
     View this article via: CrossRef PubMed Google Scholar
135. Wang C, et al. circ-BPTF serves as a miR-486-5p sponge to regulate CEMIP and promotes hypoxic pulmonary arterial smooth muscle cell proliferation in COPD. Acta Biochim Biophys Sin (Shanghai). 2023;55(3):438–448.
     View this article via: CrossRef PubMed Google Scholar
136. Yang Z, et al. Inhibition of miR-4640-5p alleviates pulmonary hypertension in chronic obstructive pulmonary disease patients by regulating nitric oxide synthase 1. Respir Res. 2023;24(1):1–13.
     View this article via: CrossRef PubMed Google Scholar
137. Alique M, et al. MicroRNA-126 regulates Hypoxia-Inducible Factor-1α which inhibited migration, proliferation, and angiogenesis in replicative endothelial senescence. Sci Rep. 2019;9(1):1–19.
     View this article via: CrossRef PubMed Google Scholar
138. Goel K, et al. Characterization of pulmonary vascular remodeling and MicroRNA-126-targets in COPD-pulmonary hypertension. Respir Res. 2022;23(1):1–10.
     View this article via: CrossRef PubMed Google Scholar
139. Gredic M, et al. Myeloid-cell-specific deletion of inducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice. Eur Respir J. 2022;59(4):2101153.
     View this article via: CrossRef PubMed Google Scholar
140. Zhu J, et al. Reactive oxygen species-dependent calpain activation contributes to airway and pulmonary vascular remodeling in chronic obstructive pulmonary disease. Antioxid Redox Signal. 2019;31(12):804–818.
     View this article via: CrossRef PubMed Google Scholar
141. Boukhenouna S, et al. Reactive oxygen species in chronic obstructive pulmonary disease. Oxid Med Cell Longev. 2018;2018:5730395.
     View this article via: CrossRef PubMed Google Scholar
142. Seimetz M, et al. NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD. Nat Metab. 2020;2(6):532–546.
     View this article via: CrossRef PubMed Google Scholar
143. Guo X, et al. NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD. BMC Pulm Med. 2018;18(1):1–20.
     View this article via: CrossRef PubMed Google Scholar
144. Qi H, et al. Epigenetic regulation by Suv4-20h1 in cardiopulmonary progenitor cells is required to prevent pulmonary hypertension and chronic obstructive pulmonary disease. Circulation. 2021;144(13):1042–1058.
     View this article via: CrossRef PubMed Google Scholar
145. Chen S, et al. The antioxidant MitoQ protects against CSE-induced endothelial barrier injury and inflammation by inhibiting ROS and autophagy in human umbilical vein endothelial cells. Int J Biol Sci. 2019;15(7):1440–1451.
     View this article via: CrossRef PubMed Google Scholar
146. Tura-Ceide O, et al. Progenitor cell mobilisation and recruitment in pulmonary arteries in chronic obstructive pulmonary disease. Respir Res. 2019;20(1):1–9.
     View this article via: CrossRef PubMed Google Scholar
147. Peinado VI, et al. Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;159(5 pt 1):1605–1611.
     View this article via: CrossRef PubMed Google Scholar
148. Günes Günsel G, et al. The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD. Nat Commun. 2022;13(1):1303.
     View this article via: CrossRef PubMed Google Scholar
149. Perros F, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011;185(3):311–321.
     View this article via: CrossRef PubMed Google Scholar
150. Jacobs M, et al. IL-10 producing regulatory B cells are decreased in blood from smokers and COPD patients. Respir Res. 2022;23(1):1–12.
     View this article via: CrossRef PubMed Google Scholar
151. Li C, et al. Regulatory B cells protect against chronic hypoxia-induced pulmonary hypertension by modulating the Tfh/Tfr immune balance. Immunology. 2023;168(4):580–596.
     View this article via: CrossRef PubMed Google Scholar
152. Eddahibi S, et al. Interleukin-6 gene polymorphism confers susceptibility to pulmonary hypertension in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006;3(6):475–476.
     View this article via: CrossRef PubMed Google Scholar
153. Joppa P, et al. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest. 2006;130(2):326–333.
     View this article via: CrossRef PubMed Google Scholar
154. Zabini D, et al. High-mobility group box-1 induces vascular remodelling processes via c-Jun activation. J Cell Mol Med. 2015;19(5):1151–1161.
     View this article via: CrossRef PubMed Google Scholar
155. Chaouat A, et al. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest. 2009;136(3):678–687.
     View this article via: CrossRef PubMed Google Scholar
156. Jandl K, et al. Reply to Wang and Zhou. Am J Respir Crit Care Med. 2023;207(6):796–798.
     View this article via: CrossRef PubMed Google Scholar
157. Jandl K, et al. Basement membrane remodeling controls endothelial function in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2020;63(1):104–117.
     View this article via: CrossRef PubMed Google Scholar
158. Fuller BM, et al. The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis. Chest. 2015;147(6):1510–1522.
     View this article via: CrossRef Google Scholar
159. Adhikari NKJ, et al. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med. 2014;42(2):404–412.
     View this article via: CrossRef PubMed Google Scholar
160. Searcy RJ, et al. The role of inhaled prostacyclin in treating acute respiratory distress syndrome. Ther Adv Respir Dis. 2015;9(6):302–312.
     View this article via: CrossRef PubMed Google Scholar
161. Raghu G, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158(9):641–649.
     View this article via: CrossRef PubMed Google Scholar
162. Raghu G, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42(6):1622–1632.
     View this article via: CrossRef PubMed Google Scholar
163. King TE, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(1):92–99.
     View this article via: CrossRef PubMed Google Scholar
164. King TE, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177(1):75–81.
     View this article via: CrossRef PubMed Google Scholar
165. Nathan SD, et al. Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study. Lancet Respir Med. 2019;7(9):780–790.
     View this article via: CrossRef PubMed Google Scholar
166. Zisman DA, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620–628.
     View this article via: CrossRef PubMed Google Scholar
167. Rivera-Ortega P, et al. Nintedanib in the management of idiopathic pulmonary fibrosis: clinical trial evidence and real-world experience. Ther Adv Respir Dis. 2018;12:1–13.
     View this article via: CrossRef PubMed Google Scholar
168. Behr J, et al. Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2020;9(1):85–95.
     View this article via: CrossRef PubMed Google Scholar
169. Nathan SD, et al. Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study. Lancet Respir Med. 2021;9(11):1266–1274.
     View this article via: CrossRef PubMed Google Scholar
170. Stolz D, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J. 2008;32(3):619–628.
     View this article via: CrossRef PubMed Google Scholar
171. Valerio G, et al. Effect of bosentan upon pulmonary hypertension in chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2009;3(1):15–21.
     View this article via: CrossRef PubMed Google Scholar
172. Blanco I, et al. Sildenafil to improve respiratory rehabilitation outcomes in COPD: a controlled trial. Eur Respir J. 2013;42(4):982–992.
     View this article via: CrossRef PubMed Google Scholar
173. Vitulo P, et al. Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: a randomized controlled multicenter clinical trial. J Heart Lung Transplant. 2017;36(2):166–174.
     View this article via: CrossRef PubMed Google Scholar
174. Lambers C, et al. Treprostinil inhibits proliferation and extracellular matrix deposition by fibroblasts through cAMP activation. Sci Rep. 2018;8(1):1–10.
     View this article via: CrossRef PubMed Google Scholar
175. Nikitopoulou I, et al. Orotracheal treprostinil administration attenuates bleomycin-induced lung injury, vascular remodeling, and fibrosis in mice. Pulm Circ. 2019;9(4):1–14.
     View this article via: CrossRef PubMed Google Scholar
176. Sawheny E, et al. Iloprost improves gas exchange in patients with pulmonary hypertension and ARDS. Chest. 2013;144(1):55–62.
     View this article via: CrossRef PubMed Google Scholar
177. Granfeldt A, et al. Senicapoc treatment in COVID-19 patients with severe respiratory insufficiency—a randomized, open-label, phase II trial. Acta Anaesthesiol Scand. 2022;66(7):838–846.
     View this article via: CrossRef PubMed Google Scholar
178. Kolb M, et al. Nintedanib plus Sildenafil in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2018;379(18):1722–1731.
     View this article via: CrossRef PubMed Google Scholar
179. Simons D, et al. Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment. J Cell Mol Med. 2011;15(3):668–678.
     View this article via: CrossRef PubMed Google Scholar
180. Tanaka K, et al. Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2009;298(3):348–L360.
     View this article via: PubMed Google Scholar
181. Collum SD, et al. Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis. Br J Pharmacol. 2017;174(19):3284–3301.
     View this article via: CrossRef PubMed Google Scholar
182. Degryse AL, et al. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2010;299(4):L442–L452.
     View this article via: CrossRef PubMed Google Scholar
183. Milara J, et al. The JAK2 pathway is activated in idiopathic pulmonary fibrosis. Respir Res. 2018;19(1):1–12.
     View this article via: CrossRef PubMed Google Scholar
184. Song X, et al. Pirfenidone suppresses bleomycin‑induced pulmonary fibrosis and periostin expression in rats. Exp Ther Med. 2018;16(3):1800–1806.
     View this article via: PubMed Google Scholar
185. Schroll S, et al. Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist Bosentan. Respir Physiol Neurobiol. 2010;170(1):32–36.
     View this article via: CrossRef PubMed Google Scholar
186. Derseh HB, et al. K_Ca3.1 channel blockade attenuates microvascular remodelling in a large animal model of bleomycin-induced pulmonary fibrosis. Sci Rep. 2019;9(1):1–11.
     View this article via: CrossRef PubMed Google Scholar
187. Cao ZJ, et al. Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A. Acta Pharmacol Sin. 2022;43(4):908–918.
     View this article via: CrossRef PubMed Google Scholar
188. Birnhuber A, et al. IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis. Eur Respir J. 2019;54(3):1900154.
     View this article via: CrossRef PubMed Google Scholar
189. Jiang B, et al. Marked strain-specific differences in the SU5416 rat model of severe pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2016;54(4):461–468.
     View this article via: CrossRef PubMed Google Scholar
190. Chaudhary KR, et al. Efficacy of treprostinil in the SU5416-hypoxia model of severe pulmonary arterial hypertension: haemodynamic benefits are not associated with improvements in arterial remodelling. Br J Pharmacol. 2018;175(20):3976–3989.
     View this article via: CrossRef PubMed Google Scholar