Matrix metalloproteinase-9 predicts pulmonary status declines in α1-antitrypsin deficiency

Omachi, Theodore A.; Eisner, Mark D.; Rames, Alexis; Markovtsova, Lada; Blanc, Paul D.

doi:10.1186/1465-9921-12-35

Cited by 39 publications

(38 citation statements)

References 53 publications

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“…This is significant because the role of MMP-12 in the development of emphysema has been clearly established (39). Although the loss of MMP-9 does not prevent cigarette smoke-induced emphysema in mice (40), enhanced expression of this protease in macrophages causes progressive air space enlargement in mice and is associated with COPD severity in humans (41,42). These results suggest that aberrant EGFR and c-Src activation could promote the development of this disease by inducing the expression of MMP-9 and MMP-12 in the lung.…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Activates the Proto-Oncogene c-Src to Promote Airway Inflammation and Lung Tissue Destruction

Geraghty

Hardigan

Foronjy

2014

Am J Respir Cell Mol Biol

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The diagnosis of chronic obstructive pulmonary disease (COPD) confers a 2-fold increased lung cancer risk even after adjusting for cigarette smoking, suggesting that common pathways are operative in both diseases. Although the role of the tyrosine kinase c-Src is established in lung cancer, less is known about its impact in other lung diseases, such as COPD. This study examined whether c-Src activation by cigarette smoke contributes to the pathogenesis of COPD. Cigarette smoke increased c-Src activity in human small airway epithelial (SAE) cells from healthy donors and in the lungs of exposed mice. Similarly, higher c-Src activation was measured in SAE cells from patients with COPD compared with healthy control subjects. In SAE cells, c-Src silencing or chemical inhibition prevented epidermal growth factor (EGF) receptor signaling in response to cigarette smoke but not EGF stimulation. Further studies showed that cigarette smoke acted through protein kinase C a to trigger c-Src to phosphorylate EGF receptor and thereby to induce mitogen-activated protein kinase responses in these cells. To further investigate the role of c-Src, A/J mice were orally administered the specific Src inhibitor AZD-0530 while they were exposed to cigarette smoke for 2 months. AZD-0530 treatment blocked c-Src activation, decreased macrophage influx, and prevented airspace enlargement in the lungs of cigarette smoke-exposed mice.Moreover, inhibiting Src deterred the cigarette smoke-mediated induction of matrix metalloproteinase-9 and -12 in alveolar macrophages and lung expression of cathepsin K, IL-17, TNF-a, MCP-1, and KC, all key factors in the pathogenesis of COPD. These results indicate that activation of the proto-oncogene c-Src by cigarette smoke promotes processes linked to the development of COPD.

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Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Activates the Proto-Oncogene c-Src to Promote Airway Inflammation and Lung Tissue Destruction

Geraghty

Hardigan

Foronjy

2014

Am J Respir Cell Mol Biol

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“…and oxygen saturation, and were also able to predict both a decline in pulmonary function and numbers of exacerbations [84]. Induced sputum analysis has found increases in MMP-9 protein and MMP-9 activity [83,85] in smokers with and without airflow obstruction.…”

Section: Series: Mmps In Lung Health and Diseasementioning

confidence: 97%

“…Plasma levels of MMP-9 appear to be increased in a 1 -trypsin deficiency-associated emphysema and in COPD [84,85], and were shown to correlate negatively with FEV1, carbon monoxide transfer factor…”

Section: Mmp-9mentioning

confidence: 99%

Matrix metalloproteinases in COPD

Churg

Zhou²,

Wright³

2011

Eur Respir J

237

116

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There is considerable evidence that matrix metalloproteinases (MMPs) are up-and/or downregulated in chronic obstructive pulmonary disease (COPD), particularly in emphysema, in which they probably participate in proteolytic attack on the alveolar wall matrix. Recent data suggest that MMPs also have major roles in driving inflammation or shutting it down, as well as modifying the release of fibrogenic growth factors, processes that are important in the genesis of the various lesions of COPD. In cigarette smoke-induced animal models of emphysema, MMP-12 appears to play a consistent and important role, whereas the data for other MMPs are difficult to interpret. In human lungs, evidence for a role for MMPs is more tenuous and there are numerous contradictions in the literature. Little is known about the effects of MMPs in small airway remodelling, smokeinduced pulmonary hypertension and chronic bronchitis, but MMP-12 participates in experimental small airway modelling. To date, the accumulated data suggest that selective inhibition of MMP-12 might be a viable therapy for emphysema and small airway remodelling, but subtle differences in the functions of MMP-12 in animals and humans mandate caution with this approach. Whether inhibition of other MMPs might be useful is unclear.

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“…Whether it predicts progression in A1ATD remains unknown at present. Other suggested biomarkers in A1ATD include MMP-9 [89] and leukotriene B4 [43]. However, further longitudinal studies are needed to establish if any of these proposed biomarkers can satisfy all the criteria needed for the development of novel therapeutic strategies in A1ATD (tablE 1) [83].…”

Section: Emphysema Risk In A1atdmentioning

confidence: 99%