Matrix metalloproteinases: all the RAGE in the acute respiratory distress syndrome.

THE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) is characterized by rapid-onset, severe lung inflammation with massive influx of polymorphonuclear neutrophils (PMNs) into the lungs and injury to the alveolar capillary barrier and is associated with a high mortality rate. There is mounting evidence that matrix metalloproteinases (MMPs) contribute to the pathogenesis of ARDS. Most MMPs implicated in the pathogenesis of ARDS promote lung inflammation and/or injury to the alveolar capillary barrier in animal models of acute lung injury (ALI). The study of Yamakawa et al. (23) in this issue of the journal is noteworthy because it has implicated two MMPs (MMP-3 and -13), which hitherto have not been well studied in ALI or ARDS, in protecting the lung from developing ALI by cleaving a novel substrate: the receptor for advanced glycation end products (RAGE). MMPs and ARDS pathogenesis. MMPs are a family of zinc-dependent proteinases with a multidomain structure. There are 23 members of this family in humans. MMPs are expressed by all cell types relevant to ARDS pathogenesis including alveolar epithelial cells, PMNs, macrophages, and fibroblasts. MMPs have been implicated in the pathogenesis of ARDS because lung levels of several MMPs are increased in patients with ALI and ARDS and lung levels of some MMPs correlate positively with adverse clinical outcomes in ARDS patients. For example, bronchoalveolar lavage (BAL) fluid (BALF) levels of collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), and stromelysin-1 (MMP-3) are elevated in patients with ALI and ARDS (9). MMP-1 and -3 may promote disease progression in ARDS since BALF levels of MMP-1 and -3 (but not MMP-2, -8, or -9) correlate positively with lung injury severity and also with multiorgan failure and mortality rates in ARDS patients (9). Although degradation of extracellular matrix proteins was believed to be the main function of MMPs for years after MMPs were first identified, more recent studies of MMP-null mice in models of ALI have shown that MMPs generally promote ALI by cleaving cytokines and chemokines to regulate the biological activities of these mediators (Table 1). Until now, only two MMPs have been shown to possess anti-inflammatory activities during ALI: 1) MMP-8, which protects mice from bacterial lipopolysaccharide (LPS)and hyperoxia-induced ALI by degrading macrophage inflammatory protein-1 (18), and 2) MMP-13, which limits lung inflammation during hyperoxia-induced ALI by inactivating monocyte chemoattractant protein-1 (19). The study of Yamakawa et al. (23) is noteworthy because it not only adds MMP-3 to this short list of MMPs having protective activities during ALI but also identifies RAGE as a potentially novel substrate for MMPs in the setting of ALI and ARDS. RAGE biology and activities during ALI. RAGE is a 35-kDa transmembrane receptor belonging to the immunoglobulin superfamily. RAGE has five domains including 1) a cytosolic domain that is responsible for signal transduction; 2) a transmembrane domain that anchors the receptor in the cell membrane; 3) a variable (V-type) domain that binds ligands; and 4) two constant (C-type) immunoglobulin-like regions domains (Fig. 1). RAGE is expressed in many tissues and cells including lung, kidney, and endothelial cells of large vessels. However, RAGE is expressed most abundantly in the lung, where it is localized exclusively to the basolateral membrane of alveolar epithelial type I (AT1) cells (Fig. 1). RAGE binds several ligands including advanced glycation end products (AGEs), high-mobility group protein B1 (HMGB1), amyloid -peptide, and members of the S100/calgranulin family of proinflammatory proteins. The binding of AGE, HBGB1, and amyloid -peptide to the ectodomain of RAGE initiates intracellular signaling leading to activation of nuclear factorB (NFB) and induction of proinflammatory gene expression (Fig. 1). Interestingly, RAGE itself is also upregulated by activation of NFB (Fig. 1). This may lead to a positive feedback cycle that amplifies tissue inflammation and injury in diseases in which levels of RAGE ligands are increased. One RAGE ligand in particular, HMGB1, is a potent mediator of ALI since it drives PMN accumulation, edema formation, and production of proinflammatory mediators in the lung (1). HMGB1 is also a mediator of lethality during endotoxemia and sepsis in mice. In humans with severe trauma, plasma HMGB1 levels correlate positively with severity of injury and progression to ALI (7). RAGE / mice are protected from systemic inflammatory response during septic shock (15). Thus HMBG1-RAGE signaling likely promotes progression to and/or increases the severity of the acute-exudative phase of ARDS. RAGE also has the potential to promote progression to the fibroproliferative phase of ARDS since RAGE / mice are protected from bleomycin-induced lung fibrosis (11). The profibrotic activities of RAGE are due to HMGB1-RAGE signaling leading to increased production of profibrotic growth factors and induction of epithelial-mesenchymal transition (Fig. 1). sRAGE and ALI/ARDS. Although RAGE is thought to function as a signaling transmembrane protein, soluble forms of RAGE (sRAGE) are generated in the lung and plasma during ALI/ARDS. In rodents with ALI, lung levels of sRAGE are increased and correlate positively with the severity of ALI (20). In human ALI patients ventilated with high tidal volumes, higher baseline plasma levels of sRAGE correlate with severity Address for reprint requests and other correspondence: C. Owen, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital/ Harvard Medical School, 855B Harvard Institutes of Medicine Bldg., 77 Ave. Louis Pasteur, Boston, MA 02115 (e-mail: [email protected]). Am J Physiol Lung Cell Mol Physiol 300: L512–L515, 2011; doi:10.1152/ajplung.00023.2011. Editorial Focus