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Published ahead of print on June 7, 2004, doi:10.1164/rccm.200404-511OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 492-498, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200404-511OC

Original Article

Tumor Necrosis Factor-{alpha} Drives 70% of Cigarette Smoke–induced Emphysema in the Mouse

Andrew Churg, Rong D. Wang, Hsin Tai, Xiaoshan Wang, Changshi Xie and Joanne L. Wright

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Andrew Churg, M.D., Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5 Canada. E-mail: achurg{at}interchange.ubc.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mice lacking tumor necrosis factor-{alpha} (TNF-{alpha}) receptors (TNFRKO mice) do not develop an inflammatory infiltrate or matrix breakdown after a single acute cigarette smoke exposure. To determine the role of TNF-{alpha} in the long-term development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice demonstrated an 11% increase in mean linear intercept; wild-type mice had a 38% increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in lavage fluid. Whole lung matrix metalloprotease (MMP)-2, MMP-9, MMP-12, MMP-13, and matrix type-1 (MT1)-MMP proteins were increased in wild-type mice, but smaller increases in MMP-12, MMP-13, and MT1-MMP were also seen in TNFRKO mice. Lavage matrix breakdown products were elevated in wild-type mice and only partially reduced by anti-neutrophil antibody, implying both neutrophil- and non–neutrophil-mediated matrix breakdown. We conclude that TNF-{alpha}–mediated processes, probably driving neutrophil influx, are responsible for approximately 70% of airspace enlargement and the majority of inflammatory cell influx/matrix breakdown in the mouse model. TNF-{alpha} causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second TNF-{alpha}–independent process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.

Key Words: emphysema • macrophage metalloelastase-12 • matrix metalloprotease • tumor necrosis factor-{alpha}

The pathogenesis of cigarette smoke–induced emphysema is an area of intensive investigation. The traditional theory is that emphysema develops through an imbalance between proteases released from smoke-induced inflammatory cells in the lower respiratory tract and the antiproteolytic defenses of the lung, a process that results in destruction of lung matrix and development of the enlarged airspaces that characterize emphysema. This theory is generally referred to as the protease–antiprotease hypothesis (reviewed in 1–3).

However, the exact cells and proteases that participate in the development of emphysema are a topic of considerable dispute. Observations that emphysema could be induced experimentally by instillation of elastases and that individuals deficient in {alpha}-1-antitrypsin developed early-onset emphysema led to the idea that neutrophils and neutrophil proteases, particularly neutrophil elastase, were the important agents (1–3). More recent reports have suggested that macrophages and macrophage-derived metalloproteases might be more important because mice lacking macrophage metalloelastase (MMP-12) are completely protected against smoke-induced emphysema (4, 5). Correlations have been reported between macrophage numbers in histologic sections and morphologic markers of tissue destruction, whereas no such correlations are found with neutrophil numbers (6, 7). Moreover, a variety of macrophage metalloproteases, including gelatinases A and B (MMP-2 and MMP-9), matrilysin (MMP-7), and MMP-12, are now known to degrade elastin and collagen (8–10). Human lungs with emphysema show higher levels of MMP-1 (interstitial collagenase), MMP-2, MMP-9, and matrix type-1 (MT1)-MMP compared with lungs without (11, 12), and the lungs of guinea pigs exposed to smoke contain increased amounts of MMP-1 (13).

Subsequent studies have made it clear that the processes of matrix breakdown and airspace enlargement that characterize emphysema are not simple effects of only one type of inflammatory cell or one protease. We found that neutrophils were required for matrix breakdown in a mouse model and that MMP-12 was required for the development of a neutrophil influx (14, 15). Despite the fact that lack of MMP-12 completely protects against emphysema, Shapiro and colleagues (5) reported that mice lacking neutrophil elastase are also approximately 60% protected, again implying interactions between neutrophils/neutrophil elastase and macrophages/MMP-12 (see DISCUSSION).

The data described previously here make clear the importance of inflammatory cell recruitment in the development of emphysema, but little is known about the mechanisms driving cell recruitment. We recently showed that mice lacking p55 and p75 tumor necrosis factor-{alpha} (TNF-{alpha}) receptors (TNFRKO mice) failed to develop an inflammatory infiltrate after acute smoke exposure and also did not show evidence of acute matrix breakdown (16). We subsequently (17) reported that TNF-{alpha} release from alveolar macrophages after smoke exposure appeared to be mediated by MMP-12, apparently because MMP-12 acted as a form of TNF-{alpha}–converting enzyme, liberating active (17 kD) TNF-{alpha} with subsequent endothelial activation and neutrophil influx.

These findings suggest that TNF-{alpha} may be central to the inflammatory events that lead to emphysema. In this article, we test this hypothesis and examine the development of emphysema in TNFRKO mice chronically exposed to smoke. An abstract of this article has been published (18).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Sources of Materials
TNFRKO mice were obtained through the courtesy of Dr. Jacques Peschon (Amgen Corporation, Seattle, WA). The original mice were created in strain 129 stock and were backcrossed x 5 generations into C57Bl/6 stock. For control animals, strain 129J mice (Charles River Laboratories, Montreal, PQ, Canada) were backcrossed x 5 generations into C57Bl/6 stock. These backcrossed animals are referred to as "wild type" in this article. 2R1 research cigarettes were obtained from the University of Kentucky.

Smoke Exposure and Lavage Procedures
Experimental groups consisted of five mice. The mice were exposed to the whole smoke from four 2R1 cigarettes using a standard smoking apparatus (14) 5 days per week for 6 months. Wild-type mice were sham smoked. At 24 hours after the last smoke exposure, mice were killed by halothane overdose, and the lungs were removed from the chest cavity. An 18-gauge catheter was inserted into the trachea, and the lungs were lavaged five times with 1 ml of ice-cold saline to obtain cell pellets for counting. Further details are provided in the online supplement.

Morphometric Measurements of Airspace Size
For morphometric analysis, the lavaged lungs were inflated with liquid agarose at a pressure of 25 cm of water, as described by Halbower and colleagues (19), cooled to allow the agarose to harden, and then fixed for 24 hours in formalin. The fixed lungs were serially sectioned in a sagittal plane, and a random slice was submitted for paraffin embedding, sectioning, and staining by hematoxylin and eosin. Measurements of mean linear intercept (Lm) and volume proportion of alveolar duct air (alveolar ducts plus alveolar sacs) were performed as described by Halbower and colleagues (19) and Kawakami and colleagues (20). Further details are provided in the online supplement.

Measurements of Matrix Breakdown
Separate sets of animals for matrix breakdown analysis were exposed to smoke as mentioned previously here and then lavaged with distilled water. Analysis of the lavage fluid for desmosine, a marker of elastin breakdown, and hydroxyproline, a marker of collagen breakdown, was performed as previously described (21).

Treatment with Anti-Neutrophil Antibodies
Additional sets of animals were exposed to smoke as described previously here for 6 months. Starting 4 days before killing, they were given 0.5 ml of anti-neutrophil antibody on a daily basis (Accurate Chemical and Scientific, Westbury, NY).

Western Blots for Matrix Metalloproteases
Additional mice were exposed to smoke for 6 months and Western blots for MMP-2, MMP-9, MMP-12, MMP-13, and MT1-MMP performed on homogenized whole lungs as described in the online supplement.

Casein Zymography
Casein zymography of lavage fluid to detect active MMP-12 was performed as described by Fernandez-Resa and colleagues (22).

Statistics
Groups were compared by analysis of variance. Values of p < 0.05 or less were considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In wild-type mice, an obvious pattern of centrilobular emphysema was present on casual inspection; similar but much less marked changes were visible in TNFRKO mice. Lm, which is a general measure of mean airspace size, was increased 38% in wild-type mice but only 11% in TNFRKO mice (Figure 1). Volume proportion of alveolar duct air, which is a more sensitive measure for assessing centrilobular emphysema, was increased 88% in wild-type mice and 28% in TNFRKO mice (Figure 1). Both these measures indicate about the same degree of protection against emphysema in TNFRKO mice: 71% when using Lm and 65% when volume proportion of alveolar duct air.



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  		Figure 1. Airspace size in wild-type (WT) mice and mice lacking tumor necrosis factor-{alpha} (TNF-{alpha}) receptors (TNFRKO) after 6 months of smoking. There is a 38% increase in Lm in WT and an 11% increase in TNFRKO (71% protection). There is an 88% increase in volume proportion of alveolar duct air in wild-type and 28% in TNFRKO (65% protection). Values are mean ± SD. *Significantly greater than control of strain, p < 0.05 or less. Ctrl = control.

 
Figure 2 shows lavage inflammatory cell counts. Neutrophils in smoke-exposed animals were increased compared with air-exposed animals in both wild-type and TNFRKO mice, but the numbers of neutrophils in the smokers were 65% less in the TNFRKO mice. Macrophages were increased approximately 30% in wild-type mice and 11% in TNFRKO mice, the latter not a statistically significant value.



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  		Figure 2. Lavage cell counts after 6 months of smoking. TNFRKO mice show a 65% decrease in lavage neutrophil levels compared with wild-type and no increase in macrophages. Values are mean ± SD. *Significantly greater than control of strain, p < 0.05 or less. MAC = macrophages; PMN = neutrophils.

 
Figure 3 shows matrix breakdown products in lavage in wild-type mice. Levels of hydroxproline and desmosine were increased twofold to threefold in smoke-exposed animals. In smoking animals treated for 4 days before killing with anti-neutrophil antibodies, levels of desmosine were decreased by 71% compared with smoking animals not given antibody, a level not statistically different from air-exposed control animals. Levels of hydroxyproline were decreased by 53% after anti-neutrophil antibody treatment, and this value was statistically greater than control (p < 0.05). Figure 4 shows matrix breakdown products in the lavage of TNFRKO mice. Smoke exposure resulted in 27% increases in lavage desmosine and 17% increases in lavage hydroproline levels; these values were reduced by anti-neutrophil antibody. None of the changes was statistically different from control values. It should be noted that the data in Figures 3 and 4 were not obtained from the same HPLC run, and the absolute values of desmosine and hydroxyproline in the two figures cannot be compared. Analysis of lavage cell counts and blood white cell counts showed that treatment with anti-neutrophil antibody reduced neutrophils to undetectable levels in both types of mice (data not shown).



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  		Figure 3. Lavage matrix breakdown products after 6 months of smoking in wild-type mice. In animals exposed to smoke, there is a twofold to threefold increase in lavage desmosine and hydroxyproline levels. Administration of anti-neutrophil antibody (anti-PMN) for 4 days before killing reduces blood and lavage neutrophil counts to zero (data not shown) and returns lavage desmosine levels to control values; however, lavage hydroxyproline levels remain significantly greater than control (53% less than in animals exposed to smoke alone). Values are mean ± SD. *Significantly greater than control, p < 0.05 or less.

 


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  		Figure 4. Lavage matrix breakdown products after 6 months of smoking in TNFRKO mice. There is a small (27% for desmosine, 17% for hydroproline) but not statistically significant increase in matrix breakdown products in animals exposed to smoke. Values are mean ± SD.

 
Figure 5 shows whole lung Western blots for MMP-2, MMP-9, pro–MMP-12 (the antibody used only detects the pro-form of the enzyme), MMP-13, and MT1-MMP. For all of these enzymes, smoke exposure produced a twofold to threefold increase in protein levels in wild-type mice. In TNFRKO mice, no increases were seen for MMP-2 and MMP-9, but a small (significant) increase was present for MMP-12, MMP-13, and MT1-MMP.



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  		Figure 5. Whole lung Western blots and densitometry for matrix metalloprotease (MMP) proteins after 6 months of smoking. All MMPs show a twofold to threefold increase in wild-type mice. A significant but smaller increase is seen for MT1-MMP and MMP-12 and MMP-13 in TNFRKO mice. The antibody used for MMP-12 detects only the 54-kD pro-form. The columns in the graphs represent the following: 1, wild-type control; 2, wild-type smoke; 3, TNFRKO control; 4, TNFRKO smoke. C1,C2=control; S1,S2= smoke. Representative data from one of two experiments are shown.

 
Figure 6 shows casein zymography to detect active MMP-12 in lavage fluid. In wild-type mice, smoke exposure more than doubled levels of active enzyme, and this was reduced by approximately 50% in animals treated with anti-neutrophil antibody, but still remained significantly greater than control. In TNFRKO mice, an increase in MMP-12 levels was also present, again with a decrease after anti-neutrophil antibody treatment.



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  		Figure 6. Lavage casein zymography to show active MMP-12 as a 22-kD band. In wild-type mice, smoke exposure roughly doubles MMP-12 levels; treatment with anti-PMN antibody reduces this by approximately 50%, but not to control levels. In TNFRKO, a similar pattern is seen. Data from three animals per group are shown. The wild-type and TNFRKO gels were not run together, and the TNFRKO gel shows much weaker signals than the wild-type gel when viewed in the original. Values are mean ± SD. *Significantly greater than control, p < 0.05 or less. Weak band at 54 kD is pro–MMP-12.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this article, we have shown that TNF-{alpha} is crucial not only to the acute response to cigarette smoke, but to the actual development of emphysema in the mouse. However, TNF-{alpha}–driven processes account for only approximately 65–70% of increases in airspace size (depending on whether one measures Lm or volume proportion alveolar duct air). TNF-{alpha}–driven processes also are responsible for the majority but not all of the inflammatory cell infiltrate and matrix breakdown effects seen in the mouse model, and TNF-{alpha} drives production of a variety of MMPs that may be important in emphysema as well. For some MMPs, however, there is increased activity in TNFRKO mice, and there is evidence of neutrophil-independent proteolysis as well.

Although the data are straightforward, interpretation of the results and creation of a coherent model are more difficult, and we do not know whether these results apply only to C57-based mice or would also be seen in strains that develop greater or lesser degrees of emphysema (23). As described in the introduction, for C57-based mice, we previously proposed that, at least in the acute setting, both MMP-12 and neutrophils are necessary for matrix breakdown, the presumed precursor of emphysema, with the link between the two being MMP-12–mediated release of TNF-{alpha} and subsequent TNF-{alpha}–mediated endothelial activation and neutrophil influx. Although this exact sequence has not been investigated in chronic models, the report of Shapiro and colleagues (5) that mice lacking neutrophil elastase are approximately 60% protected against emphysema indicated that the absence of neutrophil elastase was associated with decreased active MMP-12 levels as well as decreased macrophage influx into the lung and that in fact MMP-12 and neutrophil elastase actually destroyed each other's natural inhibitors (MMP-12 proteolytically inactivates {alpha}-1-antitrypsin, and neutrophil elastase inactivates tissue inhibitor of metalloprotease-1). Thus, that study also supports a close connection between neutrophils and MMPs in the genesis of emphysema. Our current data emphasize, as well, the idea that neutrophils play a long-term continuing role in the development of emphysema, at least in the mouse. We presume that neutrophil elastase is the most important effector in this regard, but other neutrophil serine proteases and MMPs may have a role as well.

It is particularly interesting that the present experiments yield a protection value in the range of 65 to 70% when TNF-{alpha} signaling is removed from the system and that roughly comparable protection values were found with neutrophil elastase knockout mice (60%) (5) and the serine elastase inhibitors ZD0892 (45%) (24) and {alpha}-1-antitrypsin (63%) (25); in both of the latter studies, levels of serum TNF-{alpha} were elevated with smoke exposure and returned to baseline with the elastase inhibitor. In aggregate, these observations suggest that TNF-{alpha}–driven processes account for approximately 60–70% of emphysema, most likely through the effects of TNF-{alpha} on PMN recruitment. However, TNF-{alpha} produces complex patterns of both inflammation and inhibition of inflammation (26), and other TNF-{alpha}–mediated effects may well be present in the smoke model.

It is also interesting in this context to note the recent report of Vuillemenot and colleagues (27). They produced doxycycline-inducible TNF-{alpha} transgenic mice with the transgene under the control of the SpC promotor. When doxycyline was administered, they found an increase in lung inflammatory cells and the rapid development of emphysema with increases in Lm of approximately 35 to 50% at various time points. However, the emphysema was no more severe after 9 months of doxycycline than after 1 month, implying that TNF-{alpha} has a distinct but limited ability to cause emphysema, results that are consistent with our present data.

The exact effects of MMPs in the pathogenesis of emphysema are less clear. We examined levels of five different MMPs that have been suggested to play possible roles in emphysema in humans. MMP-13 was substituted for MMP-1 because murine MMP-1 appears to have different functions, and murine MMP-13 is probably the closest analogue to the human protease (28). For all of the MMP's protein levels were increased in the wild-type mice. In a sense, our results are not surprising, as TNF-{alpha} is a well established driver of production of a number of MMPs, including MMP-12 (29, 30). Our data do raise the possibility that TNF-{alpha} and MMP-12 (and possibly other MMPs, because a number of MMPs have TNF-{alpha}–releasing activity, at least in vitro) (31) may be involved in a feedback loop, with smoke causing enhanced production/release of MMP-12, which then liberates TNF-{alpha} (17), which in turn increases MMP-12 production.

However, there were also increases in MT1-MMP, MMP-12, and MMP-13 protein in the TNFRKO mice, indicating that there is a TNF-{alpha}–independent process that leads to increased MMP production in these animals as well. In our previous study (16), we observed that TNFRKO mice had no inflammatory cell response after a single acute smoke exposure. In this chronic study, TNFRKO mice had a much reduced but still distinct increase in lavage neutrophils compared with wild-type mice; this finding again implies that during the development of emphysema, there is a second long-term process that drives neutrophil influx independent of the actions of TNF-{alpha} and that may be related to all or part of the remaining 30% of airspace enlargement.

The nature of this second process is unclear. One possibility is that it reflects smoke-induced apoptosis of alveolar epithelial cells, an event that has been reported in human lungs with emphysema (32–34). This theory requires several intermediate steps, because apoptosis per se should not evoke a neutrophil response. However, Aoshiba and colleagues (35) have reported that apoptosis induced by the administration of caspase 3 in the lung is associated with increased elastase activity and elastin breakdown and that breakdown can be partially prevented by E-64, an inhibitor of cysteine proteases. Because elastin and collagen fragments are chemotactic for neutrophils and macrophages (36, 37), apoptosis-induced matrix fragments might be the source of the residual neutrophil infiltrate. It is intriguing that Kasahara and colleagues (33) produced a pattern resembling centrilobular emphysema by systemic administration of a vascular endothelial growth factor–receptor antagonist, supporting the idea that apoptosis could play a role in the development of the lesions seen in our mice.

The data presented here indicate that there is residual matrix breakdown not associated with neutrophils, because treatment of the mice with anti-neutrophil antibody, a process that reduces blood and lavage neutrophil levels to zero, still leaves lavage hydroxyproline levels elevated above control (non–smoke-exposed) values. These findings raise the possibility that MMPs may play a role in the residual 30% of emphysema that appears not to be associated with TNF-{alpha} signaling. A similar conclusion can be drawn from data presented by Shapiro and colleagues: neutrophil elastase knockout provides 60% protection against airspace enlargement (5), whereas MMP-12 knockout is 100% protective (4, 5), as is the broad-spectrum MMP inhibitor RS113456 (38), again implying a second process related to MMPs. Our casein zymography data indicate that smoke-enhanced MMP-12 activity is in part dependent on the presence of neutrophils; Shapiro and colleagues (5) produced very similar data and showed that neutrophil elastase activated MMP-12. In our study, however, there is still residual (above control) MMP-12 activity after neutrophil depletion. As well, even in TNFRKO mice there is increased MMP-12, MMP-13, and MT1-MMP production/activity. Thus, this second process might simply be direct MMP-12 (or conceivably other MMP)–mediated matrix breakdown. Whether elastolytic MMPs actually cause elastin breakdown in vivo as opposed to functioning as effectors that release signaling molecules such as TNF-{alpha} has been a controversial topic (31), but a recent report by Filippov and colleagues (39) provides evidence that MMPs can degrade matrix in vivo. What the driving force behind this non–TNF-{alpha}–mediated induction of MMPs might be is unclear; one possibility is that it is a direct effect of smoke on alveolar macrophages, an idea perhaps implied in the results published by Shapiro and colleagues (5) as well.

Whatever the mechanism, the current experiments suggest that, at least in the mouse, emphysema has two components: the majority of matrix breakdown and emphysema is mediated via TNF-{alpha} and neutrophils, with neutrophil elastase as the presumed major effector and MMPs (at least MMP-12 and possibly other MMPs) serving to release active TNF-{alpha}. The residual matrix breakdown has a different pathogenesis that may be related to other types of proteases and/or direct MMP destruction of matrix.


   FOOTNOTES
 
Supported by grant MOP 42,539 from the Canadian Institutes of Health Research and in part by an infrastructure grant to the Centre for Health and Environmental Research from the Michael Smith Foundation.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; R.D.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; H.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; X.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; C.X. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; J.L.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this article.

Received in original form April 17, 2004; accepted in final form June 7, 2004


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 METHODS
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 DISCUSSION
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