Tobacco smoke-induced lung emphysema in guinea pigs is associated with increased interstitial collagenase

Abstract

We examined the expression of interstitial collagenase and its enzymatic activity in lung damage induced by tobacco smoke. Guinea pigs were exposed to the smoke of 20 cigarettes per day from 1-8 wk. Age-matched guinea pigs were used as controls. At 6 and 8 wk of smoke exposure, lungs exhibited interstitial and peribronchiolar inflammation and moderate emphysematous changes. In situ hybridization of injured lungs revealed patchy expression of collagenase mRNA mainly in macrophages but also in alveolar epithelial and interstitial cells. Immunoreactive protein was detected in alveolar macrophages and in the alveolar walls and interstitium. Collagenolytic activity increased beginning in the 4th wk of exposure (0.7 +/- 0.43 micrograms collagen degraded/mg collagen incubated relative to 0.23 +/- 0.14 in controls; P < 0.05). At 6 and 8 wk, values were 0.85 +/- 0.34 and 0.98 +/- 0.33 compared with 0.25 +/- 0.11 and 0.26 +/- 13 in controls (P < 0.005 and 0.001). Collagen concentration decreased from 50.7 +/- 8.5 mg/g dry wt in control lungs to 40.2 +/- 5.0 and 42.9 +/- 6.0 at 6 and 8 wk of exposure, respectively (P < 0.05). These results strongly suggest that increased interstitial collagen degradation plays a role in the development of lung emphysema.

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

“…The present study links this same kinase pathway to increased MMP-1 expression seen in emphysema and alveolar destruction (10). The MAP kinase pathway is also implicated in apoptosis (37-39), a cell death mechanism associated with emphysema (14,40,41). Together, these studies suggest a central role for ERK in cigarette smoke-induced MMP-1 activity in lung epithelia and in multiple emphysema-associated pathologies.…”

“…Evidence from human tissue and animal models support a role for collagenolytic enzymes in emphysema pathogenesis (9,10,13). Elevated MMP-1 levels and decreased pulmonary collagen content are measured in guinea pigs after cigarette smoke exposure (12,14). Transgenic mice expressing human collagenase (MMP-1) develop emphysematous changes in their lungs (10) caused by months of proteolytic damage to the lung parenchyma (15).…”

Matrix Metalloproteinase-2 Protein in Lung Periphery Is Related to COPD Progression

“…In guinea pigs, exposure to cigarette smoke produces emphysematous changes that are associated with increased levels of collagenase messenger RNA, resulting in collagen loss. 34 In mice exposed to cigarette smoke, the lack of MMP-12 activity prevents emphysema development and macrophage infiltration. 9,10 In humans, an analysis of protease production by alveolar macrophages in vitro has shown an increased expression of MMP-9 and MMP-12 in subjects with emphysema.…”

Matrix metalloproteinases in COPD

“…Increased whole lung MMP-1 mRNA and protein has been demonstrated in human and guinea pig emphysema [48,76,77], with increased immunoreactivity found in macrophages and in airway epithelium. GOSSELINK et al [51] reported that MMP-1 gene expression increases in the parenchyma from GOLD stage 0 to 3/4, although the magnitude of the difference overall was fairly small.…”