The Role of Matrix Metalloproteinase-9 in Cigarette Smoke–induced Emphysema

Abstract

Rationale: Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction. Objectives: To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. Methods: Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury. Measurements and Main Results: Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage. Conclusions: These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).Keywords: pulmonary disease, chronic obstructive; laser capture microdissection; mice, knockout Several studies have implicated matrix metalloproteinase-9 (MMP-9, gelatinase B, type IV collagenase B), in emphysema and chronic obstructive pulmonary disease (COPD) pathogenesis (1-5). MMP-9 can be accurately measured and is an elastolytic protease that is produced in large quantities by inflammatory cells, thus making it suitable for investigation in emphysema (5-7). However, because the pathophysiology of emphysema follows such an indolent course, developing over decades in response to cigarette smoke, a link between MMP-9 activity and alveolar destruction is lacking.Mouse models have identified several MMPs that cause airspace enlargement by overexpression (8, 9), or that prevent airspace enlargement by gene deletion in smoking models (10). The recent discovery that mice transgenically altered to overexpress human MMP-9 in alveolar macrophages develop progressive airspace enlargement (8) adds importance to the e...

Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis

“…More importantly, holistic iNOS inhibition is likely to compromise physiological functions based on multiple organ cross-talk involving the lung, which can severely disrupt the overall cellular and systemic responses governing the etiopathogenesis of CS-induced emphysema (44,45), a factor that could well account for the difference in observations between the above study (23) and that of ours. Emphysema is also characterized by increased proteolytic degradation of CS-modified lung proteins, primarily by the metalloproteinase, MMP-9, present in the lung (30). Here also, ascorbate was found to effectively reduce the CS-induced up-regulation of MMP-9.…”

“…1B) and destructive index (DI) (Fig. 1C) of the lung alveolar air-space expansion, along with extensive breakdown of the major lung structural protein, elastin, and overexpression of MMP-9, the primary lung metalloproteinase involved in protein degradation during emphysema (30) (Fig. 1E and Fig.…”

“…Moreover, our finding that vitamin C cannot only scavenge the harmful CS oxidant(s) that inflict direct lung injury but can also attenuate the associated cellular response(s) modestly contributing to the lung damage and suppress the up-regulation of matrix-metalloproteinase-9 (MMP-9), the major lung protease involved in the damage (30), also underscores the prospects of achieving comprehensive prevention of CS-induced emphysema using this antioxidant.…”

The role of matrix metalloproteinases and polymorphisms of their genes in the development of coronary heart disease

“…Відомо, що експресія ММР-9 підвищена у тканинах, де відбувається процес ремо-делювання та ангіогенезу: в судинах при ГКС [14 ˗ 16], у паренхімі легень та бронхах при емфіземі легень [17][18][19][20], артритах [21], діабетичній ангіопатії [22], а також у ткани-нах пухлин, що прогресують [22,23]. Висо-кий вміст ММР-9 є предиктором серцево-судинної летальності [24,25] разом із С-реактивним білком (СРБ), IL-6 ˗ маркером нестабільного перебігу ІХС [16].…”

“…ММР-3 сприяє cинтезу ТФР-β, який є хемоатрактантом для моноцитів, вивільняю-чи його з матриксу. Показано, що нікотин може індукувати синтез ММР ГМК [17]. Вивчали участь цього ензиму в розвитку ГКС [28][29][30], причому Wu та співавт.…”