TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice
Peter Baluk, … , David J. Shealy, Donald M. McDonald
Peter Baluk, … , David J. Shealy, Donald M. McDonald
Published September 14, 2009
Citation Information: J Clin Invest. 2009;119(10):2954-2964. https://doi.org/10.1172/JCI37626.
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Research Article Pulmonology

TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice

Abstract

Inflammation is associated with blood vessel and lymphatic vessel proliferation and remodeling. The microvasculature of the mouse trachea provides an ideal opportunity to study this process, as Mycoplasma pulmonis infection of mouse airways induces widespread and sustained vessel remodeling, including enlargement of capillaries into venules and lymphangiogenesis. Although the mediators responsible for these vascular changes in mice have not been identified, VEGF-A is known not to be involved. Here, we sought to determine whether TNF-α drives the changes in blood vessels and lymphatics in M. pulmonis–infected mice. The endothelial cells, but not pericytes, of blood vessels, but not lymphatics, were immunoreactive for TNF receptor 1 (TNF-R1) and lymphotoxin B receptors. Most TNF-R2 immunoreactivity was on leukocytes. Infection resulted in a large and sustained increase in TNF-α expression, as measured by real-time quantitative RT-PCR, and smaller increases in lymphotoxins and TNF receptors that preceded vessel remodeling. Substantially less vessel remodeling and lymphangiogenesis occurred when TNF-α signaling was inhibited by a blocking antibody or was silenced in Tnfr1–/– mice. When administered after infection was established, the TNF-α–specific antibody slowed but did not reverse blood vessel remodeling and lymphangiogenesis. The action of TNF-α on blood vessels is probably mediated through direct effects on endothelial cells, but its effects on lymphangiogenesis may require inflammatory mediators from recruited leukocytes. We conclude that TNF-α is a strong candidate for a mediator that drives blood vessel remodeling and lymphangiogenesis in inflammation.

Authors

Peter Baluk, Li-Chin Yao, Jennifer Feng, Talia Romano, Sonia S. Jung, Jessica L. Schreiter, Li Yan, David J. Shealy, Donald M. McDonald

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Figure 5

Blood vessel remodeling, lymphangiogenesis, and leukocyte influx after blocking TNF signaling.

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Blood vessel remodeling, lymphangiogenesis, and leukocyte influx after b...
(A) Extensive blood vessel remodeling and lymphangiogenesis in trachea of WT 14-day M. pulmonis–infected mouse. (B) Little vascular remodeling or lymphatic growth in infected Tnfr1–/– mouse. Scale bar: 200 μm. (C and D) Area density of blood vessels (C) and lymphatics (D) in WT mice treated with anti–TNF-α function–blocking antibody and in Tnfr1–/– (R1–/–) mice infected for 14 days. (E) Bronchial lymph node weight in anti–TNF-α antibody–treated WT mice and in infected Tnfr1–/– mice. P < 0.05, significantly different from (*) pathogen-free or (†) WT infected groups. Anti-TNF Ab, blocking antibody against mouse TNF-α. (F) qRT-PCR measurement of VEGF-A, -C, -D in tracheas of pathogen-free and 14-day infected WT and Tnfr1–/– mice. Expression of VEGF-C, but not VEGF-D is increased in infected WT mice, but not in infected Tnfr1–/– mice. VEGF-A expression is not increased in any infected airways. (G–J) H&E-stained sections of mouse lungs. (G) WT pathogen-free mouse has few H&E-stained leukocytes in lung parenchyma or airway lumen (*). (H–J) 14-day M. pulmonis–infected mice. (H) WT untreated mouse has extensive peribronchial cuffing and leukocytes in airway lumen (*) and lung parenchyma. Leukocyte influx is less prominent in infected WT mouse treated with TNF-α function–blocking antibody (I) and in infected Tnfr1–/– mouse (J). Scale bar: 50 μm.