Matrix Metalloproteinases and Protein Tyrosine Kinases

Abstract

Acute lung injury (ALI) and ARDS fall within a spectrum of pulmonary disease that is characterized by hypoxemia, noncardiogenic pulmonary edema, and dysregulated and excessive infl ammation. While mortality rates have improved with the advent of specialized ICUs and lung protective mechanical ventilation strategies, few other therapies have proven eff ective in the management of ARDS, which remains a signifi cant clinical problem. Further development of biomarkers of disease severity, response to therapy, and prognosis is urgently needed.Several novel pathways have been identifi ed and studied with respect to the pathogenesis of ALI and ARDS that show promise in bridging some of these gaps. This review will focus on the roles of matrix metalloproteinases and protein tyrosine kinases in the pathobiology of ALI in humans, and in animal models and in vitro studies. These molecules can act independently, as well as coordinately, in a feed-forward manner via activation of tyrosine kinase-regulated pathways that are pivotal in the development of ARDS. Specifi c signaling events involving proteolytic processing by matrix metalloproteinases that contribute to ALI, including cytokine and chemokine activation and release, neutrophil recruitment, transmigration and activation, and disruption of the intact alveolar-capillary barrier, will be explored in the context of these novel molecular pathways.CHEST 2014; 146 (4): 1081 -1091 ABBREVIATIONS : ALI 5 acute lung injury ; ECM 5 extracellular matrix ; EGFR 5 epidermal growth factor receptor ; LPS 5 lipopolysaccharide ; MMP 5 matrix metalloproteinase ; NRTK 5 nonreceptor tyrosine kinase ; PDGF 5 platelet-derived growth factor ; PDGFR 5 platelet-derived growth factor receptor ; PTK 5 protein tyrosine kinase ; RTK 5 receptor tyrosine kinase ; SFK 5 Src family kinase ; VEGF 5 vascular endothelial growth factor ; VEGFR 5 vascular endothelial growth factor receptor ; VILI 5 ventilatorinduced lung injury Manuscript

Matrix Metalloproteinase‐9 Production following Cardiopulmonary Bypass Was Not Associated with Pulmonary Dysfunction after Cardiac Surgery

“…The released proteolytic enzymes, such as matrix metalloproteinase- (MMP-) 9, degrade alveolar basement membrane and matrix [ 5 ], facilitating neutrophil transmigration and protein extravasation into the interstitial tissue of lung [ 6 ]. Consequently, injury to the alveolar endothelium and alveolar-capillary barrier dysfunction as central events in the pathogenesis of acute lung injury [ 7 ] are manifested with postoperative pulmonary edema and abnormal gas exchange after cardiac surgery with CPB.…”

Differential Susceptibility of Human Sp-B Genetic Variants on Lung Injury Caused by Bacterial Pneumonia and the Effect of a Chemically Modified Curcumin

“…In particular, inducible MMPs are activated by pulmonary infection, accelerating connective tissue degradation and exacerbating lung (35). MMP-2 is secreted from neutrophils and macrophages as a 72-kDa pro-form that is cleaved into a 64-kDa active form; the corresponding pro- and active forms of MMP-9 have masses of 92 kDa and 83 kDa, respectively.…”

Alveolar MMP28 is Associated With Clinical Outcomes and Measures of Lung Injury in Acute Respiratory Distress Syndrome

“…MMPs have been shown to activate, inactivate, or modify the bioavailability of key cytokines and chemokines involved in ARDS pathogenesis [5,9]. Therefore, we next tested whether Day 1 BALF (Fig.…”

“…Indeed, BALF MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 have all been associated with the presence or severity of ARDS [6][7][8]. The relationship between these MMPs and ARDS may be mediated by neutrophil chemotaxis [9]. Macrophages express a unique repertoire of MMPs based on exposure to select stimuli and their polarized states such as "M1-like" or "M2-like" [10].…”