Matrix metalloproteinases and protein tyrosine kinases: potential novel targets in acute lung injury and ARDS

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 inflammation. While mortality rates have improved with the advent of specialized ICUs and lung protective mechanical ventilation strategies, few other therapies have proven effective in the management of ARDS, which remains a significant clinical problem. Further development of biomarkers of disease severity, response to therapy, and prognosis is urgently needed. Several novel pathways have been identified 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. Specific 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.

Figure 1 –

Coordinate roles of MMPs and tyrosine kinases in control of lung inflammation. MMPs can release cytokines and growth factors from pools bound to the ECM, leading to increased local and systemic levels of these mediators. EGF is used as an example of this mechanism. Additionally, MMPs and other proteinases can cleave membrane-bound molecules generating active mediators such as cytokines and growth factors that trigger tyrosine kinase-dependent signaling pathways. TGF-α is used as an example of this mechanism. ECM = extracellular matrix; EGF = endothelial growth factor; EGFR = endothelial growth factor receptor; MMP = matrix metalloproteinase; TGF = transforming growth factor.

Figure 2 –

Regulation of lung inflammation. MMPs and protein tyrosine kinases (PTKs) can influence inflammatory responses in several ways. MMPs can be secreted from various cell types, including fibroblasts, macrophages, platelets, and epithelial cells (green arrows). MMPs can act on multiple targets (blue arrows). MMPs can cleave chemokines, such as CXCL7, resulting in enhanced chemotactic responses. They can also proteolytically process cytokines, leading to their activation, including TNF-α, TGF-β, and IL-1β. MMPs can also proteolytically cleave and activate receptor tyrosine kinases) and/or their ligands, triggering downstream proinflammatory signaling pathways. PTK signaling, including through SFKs, can result in proinflammatory responses such as degranulation of recruited neutrophils. SFK = Src family kinase; TNF = tumor necrosis factor. See Figure 1 legend for expansion of other abbreviations.

Figure 3 –

Increased vascular permeability. Protein tyrosine kinase signaling enhances vascular permeability in several ways. Signaling via receptor tyrosine kinases and nonreceptor tyrosine kinases, including VEGFR and Src, results in phosphorylation of β-catenin and subsequent dissociation of VE-cadherin homodimers, which loosens cell-cell contacts. Src also phosphorylates and activates MLCK, causing alterations in the cytoskeleton and changes in endothelial cell structure and shape, leading to increased endothelial permeability. MLCK = myosin light chain kinase; VE = vascular endothelial; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.

Figure 4 –

Breach of epithelial barrier. MMPs can disrupt various components of the epithelial barrier, allowing for transcellular passage of edema fluid and proteins, including proteinases such as MMPs. MMPs can also cleave the basement membrane, resulting in release of type 4 collagen fragments; and disrupt tight and adherens junctions, loosening cell-cell contacts. MMP secretion can also activate various RTKs, such as EGFR and PDGFR, leading to proinflammatory downstream signaling. PDGFR = platelet-derived growth factor receptor; RTK = receptor tyrosine kinase. See Figure 1 legend for expansion of other abbreviations.