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. 2003 Dec;163(6):2329-35.
doi: 10.1016/S0002-9440(10)63589-4.

Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice

Steven D Shapiro  1 , Nir M Goldstein, A McGarry Houghton, Dale K Kobayashi, Diane Kelley, Abderazzaq Belaaouaj
Affiliations

Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice

Steven D Shapiro et al. Am J Pathol. 2003 Dec.

"VSports app下载" Abstract

To address the role of neutrophil elastase in pulmonary emphysema, neutrophil elastase-deficient mice and wild-type littermate controls were exposed to long-term cigarette smoke. Compared to wild-type littermates, mice that were deficient in neutrophil elastase were significantly protected (59%) from the development of emphysema VSports手机版. Previously, we demonstrated complete protection from emphysema in the absence of macrophage elastase. Further analysis revealed several interactions between these two elastases. Each elastase inactivated the endogenous inhibitor of the other, with neutrophil elastase degrading tissue inhibitor of metalloproteinase-1, and macrophage elastase degrading alpha-1-antitrypsin. Cigarette smoke-induced recruitment of both neutrophils and monocytes was impaired in the absence of neutrophil elastase. Moreover, there was less macrophage elastase activity secondary to decreased macrophage accumulation in neutrophil elastase-deficient mice. This study demonstrates a direct role for neutrophil elastase in emphysema and highlights the interdependence of the proteinases and inflammatory cells that mediate lung destruction in response to cigarette smoke. .

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Figures

Figure 1.
Figure 1.
NE−/− mice have less cigarette smoke-induced emphysema than wild-type mice. Lungs from wild-type mice (NE+/+) and NE-deficient mice (NE−/−) were exposed to cigarette smoke for 6 months. Lungs from these mice and age-matched non-smoke-exposed control mice were inflated to 25 cm H2O and mid-sagittal slices stained with H&E as described in “Materials and Methods.” Note airspace enlargement in response to cigarette smoke exposure in NE+/+ mice and partial protection in NE−/− smoke-exposed mice.
Figure 2.
Figure 2.
Neutrophil elastase is involved in inflammatory cell recruitment in response cigarette smoke. A: Neutrophils that underwent transvascular migration to the alveolar space were quantified by bronchoalveolar lavage. Note, NE and MMP-12 did not affect recruitment in non-smoke-exposed mice (solid bars). However, NE but not MMP-12 is required for neutrophil migration in response to cigarette smoke (hatched bars). Statistically, there were more neutrophils in wild-type (WT) non-smoke-exposed (NS) versus smoke exposed (Sm)(P < 0.01), and in MMP-12−/− NS versus MMP-12−/− Sm (P < 0.01), but not NE−/− NS versus NE−/− Sm. However, NE Sm had significantly fewer neutrophils than WT Sm (P < 0.01). B: Tissue macrophage counts were assessed by immunhistochemical (mac-3) staining of mid-sagittal sections and equalized for alveolar tissue density. Note, cigarette smoke exposure increased macrophages in WT mice (WT NS versus WT Sm, P < 0.001) and NE−/− mice (NE−/− NS versus NE−/− Sm, P = 0.04), but not MMP-12−/− mice (MMP-12−/− NS versus MMP-12−/− Sm, P = 0.5). However, macrophage accumulation in response to cigarette smoke was inhibited 60% in NE−/− mice (WT Sm versus NE−/− Sm, P < 0.05), and 85% in MMP-12−/− mice (WT Sm versus MMP-12−/− Sm, P < 0.01). At least 10 mice were used for each group. Bars represent SE.
Figure 3.
Figure 3.
Proteinase activity in lungs of mice exposed to cigarette smoke. Perfused whole lung homogenates were subjected to casein zymography as described. Each lane represents equally pooled samples from three lungs of the given group. Note enhanced activity of fully processed MMP-12 (∼22 kd) in wild-type (WT) mice exposed to cigarette smoke (Sm) compared to non-smoke-exposed (NS). In the absence of NE (NE−/−), mice had markedly less active 22-kd MMP-12 and somewhat more pro-MMP-12 (migrating at ∼54 kd) in response to cigarette smoke than did wild-type mice (NE+/+). Also visible is a band migrating at ∼78 kd in all lanes that is likely an aspartyl proteinase based on inhibition pattern.
Figure 4.
Figure 4.
TIMP activity in response to cigarette smoke: evidence for NE-mediated TIMP degradation. Perfused whole lung extracts were subjected to reverse zymography. Protection from proteolytic activity is indicated by presence of gelatin (dark bands) at molecular migration of TIMPs on the blot. Note the presence of larger amounts of a 27.5-kd inhibitor, TIMP-1, in mice lacking NE. Again, each lane represents equally pooled samples from three lungs of the given genotype and exposure.
Figure 5.
Figure 5.
α1AT expression in response to cigarette smoke: evidence for MMP-12-mediated α1AT degradation. Serum and saline perfused (through right ventricle) lung tissue extracts were obtained following 6 months of cigarette smoke exposure (Sm). Age-matched sham or non-smoke-exposed (NS) mice were used as controls. Again, each lane represents equally pooled samples from three lungs. Equal amounts of protein were then subjected to Western analysis using an antibody specific for α1AT. Top: Blood serum α1AT levels were at least as prominent in cigarette smoke-exposed (Sm) lungs compared to non-smoke-exposed (NS) in both wild-type and MMP-12−/− mice. Bottom: Lung α1AT levels are decreased (by 50%) in response to cigarette smoke in wild-type as compared to MMP12−/− mice.
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