Viral infections have more severe consequences in patients who have been exposed to cigarette smoke (CS) than in those not exposed to CS. For example, in chronic obstructive pulmonary disease (COPD), viruses cause more severe disease exacerbation, heightened inflammation, and accelerated loss of lung function compared with other causes of disease exacerbation. Symptomatology and mortality in influenza-infected smokers is also enhanced. To test the hypothesis that these outcomes are caused by CS-induced alterations in innate immunity, we defined the effects of CS on pathogen-associated molecular pattern–induced (PAMP-induced) pulmonary inflammation and remodeling in mice. CS was found to enhance parenchymal and airway inflammation and apoptosis induced by the viral PAMP poly(I:C). CS and poly(I:C) also induced accelerated emphysema and airway fibrosis. The effects of a combination of CS and poly(I:C) were associated with early induction of type I IFN and IL-18, later induction of IL-12/IL-23 p40 and IFN-γ, and the activation of double-stranded RNA-dependent protein kinase (PKR) and eukaryotic initiation factor-2α (eIF2α). Further analysis using mice lacking specific proteins indicated a role for TLR3-dependent and -independent pathways as well as a pathway or pathways that are dependent on mitochondrial antiviral signaling protein (MAVS), IL-18Rα, IFN-γ, and PKR. Importantly, CS enhanced the effects of influenza but not other agonists of innate immunity in a similar fashion. These studies demonstrate that CS selectively augments the airway and alveolar inflammatory and remodeling responses induced in the murine lung by viral PAMPs and viruses.
Min-Jong Kang, Chun Geun Lee, Jae-Young Lee, Charles S. Dela Cruz, Zhijian J. Chen, Richard Enelow, Jack A. Elias
Submitter: Jack Elias | jack.elias@yale.edu
Authors: Min-Jong Kang, Charles Dela Cruz, Chjun Geun Lee
Yale University School of Medicine
Published March 30, 2009
We are pleased that Drs. Mitzner and Weibel found our study to be a very provocative article dealing with the interactions of cigarette smoke and viral infections in the pathogenesis of emphysema. In our study, we used airspace chord length (mean linear intercept: Lm) and lung volume changes as indices of emphysematous alveolar remodeling in mice. Although there has been a lot of debate over the proper application of morphometric analyses to quantitate emphysematous changes in animal models and in humans (1, 2), a number of studies strongly support the mean linear intercept (Lm) as a reliable index of pulmonary emphysema (2). As pointed out, previous investigators reported a simple mathematical relationship between alveolar surface area, lung volume (V) and Lm (Lm= 4V/surface Area) (3). However, we do not believe this mathematical equation can be considered the gold standard for the diagnosis of emphysema. Substantial discrepancies between surface area measurements and Lm values have been described in studies of emphysematous lungs. Specifically, Thurlbeck demonstrated that the internal alveolar surface area (ISA; measured at 25 cm H2O or total lung capacity) of most human lungs with emphysema fell within the normal range and that the Lm was a more reliable index to distinguish between normal and emphysematous tissues (4). Similar studies from other investigators also demonstrated that the ISA measurement was the least reliable index of emphysema (5) and Hogg and colleagues demonstrated that alveolar surface area was only decreased in severe cases of emphysema (6). These studies clearly highlight the poor sensitivity of this assessment in the diagnosis of emphysema and the practical difficulties in the simple application of this theoretical equation to the interpretation of complex human and experimental specimens. In accord with these complexities, surface area measurements are not used clinically to diagnose human emphysema. Drs. Mitzner and Weibel, also quote old literature to suggest that emphysema is an irreversible process due to destruction of alveolar walls. We agree that tissue destruction is an integral aspect of the pathogenesis of this disease. In accord with this concept we have convincingly shown alveolar wall destruction in our murine model (Figs 2 and Fig 11). We further demonstrated impressive levels of epithelial apoptosis at these sites of pathology that likely generate these destructive alterations (Figs.9-11, S3). Lastly, it is important to point out that the concept that emphysema are irreversible is antiquated and defeatist. The alterations in emphysema are the result of the antagonistic effects of injury and repair. If the latter can be augmented by interventions that increase repair and or regeneration true emphysema may actually be a reversible process. Experimental data illustrating this concept have already been reported (7, 8). Therefore, we do not agree with the letter’s final conclusion because it is drawn on the basis of a mathematical equation that does not appropriately consider the complexity of the emphysematous response, ignores the readily apparent alveolar damage in our modeling system and does not include important concepts relating to the balance of injury and repair in the lung.
Jack A. Elias
Min-Jong Kang
Charles Dela Cruz
Chjun Geun Lee
Submitter: Wayne Mitzner | wmitzner@jhsph.edu
Authors: Ewald Weibel
The Johns Hopkins School of Hygiene and Public Health Division of Physiology
Published March 23, 2009
We congratulate Dr. Kang and colleagues for a very provocative article dealing with the interaction
of cigarette smoke and viral infections on mechanisms that may underlie the pathogenesis of
emphysema (1). However, we wish to point out one methodological aspect of this work that will
affect the interpretation. To detect the occurrence of emphysema mean airspace chord length is
measured and reported in several graphs; in Figs. 2 and 11 changes in lung volume are also
reported. Figures 2B and 2C, and similarly in Fig.11, show increases in both the mean chord length
(Lm) and mean lung volume (V) in two of the experimental groups, and these increases are used as
evidence of emphysema. Since both of these increases are roughly proportional, this suggests that
the alveolar surface area, calculated as 4V/Lm (2, 3), was actually not changed. However, in
emphysema there should be an irreversible loss of surface area by destruction of alveolar walls (4),
but the figures presented confirm that this was not found with the insults in this study. The
increased Lm simply reflects more highly inflated airspaces as a result of higher volumes of the
fixed lung. From the methodological point of view this shows the importance of observing
sampling rules of stereology, mainly the consideration of changes in the reference parameters, here
the lung volume (5). That the virus and cigarette smoke caused some functional change is clear,
since the increased compliance of the lung allowed greater inflation at the same pressure, but
emphysema is more than just increased lung compliance. Therefore, the acute changes observed in
this paper might simply reflect a combination of the relatively short-term irritant and inflammatory
insults, and may have little relation to what occurs in clinical emphysema.
Wayne Mitzner, Johns Hopkins University
Ewald Weibel, University of Bern