ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

Abstract

Sun C, Beard RS Jr, McLean DL, Rigor RR, Konia T, Wu MH, Yuan SY. ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice. Am J Physiol Lung Cell Mol Physiol 304: L135-L142, 2013. First published November 16, 2012 doi:10.1152/ajplung.00133.2012.-ADAM15 is a disintegrin and metalloprotease recently implicated in cancer and chronic immune disorders. We have recently characterized ADAM15 as a mediator of endothelial barrier dysfunction. Whether this molecule contributes to acute inflammation has not been evaluated. The purpose of this study was to investigate the role of ADAM15 in mediating pulmonary microvascular leakage during acute inflammatory injury. Immunofluorescent staining and Western blotting revealed that the endothelium was the main source of ADAM15 in lung tissue. In a mouse model of acute lung injury induced by lipopolysaccharide (LPS), upregulation of ADAM15 was observed in association with pulmonary edema and neutrophil infiltration. The LPS-induced inflammatory injury, as demonstrated by bronchoalveolar lavage neutrophil count, lung wet-to-dry weight ratio, and myeloperoxidase activity, was significantly attenuated in Adam15 Ϫ/Ϫ mice. Studies with primary cell culture demonstrated abundant ADAM15 expression in endothelial cells (ECs) of mouse lung but not in neutrophils. Deficiency of ADAM15 in ECs had no obvious effect on basal permeability but significantly attenuated hyperpermeability response to LPS as evidenced by albumin flux assay and measurements of transendothelial electrical resistance, respectively. ADAM15 deficiency also reduced neutrophil chemotactic transmigration across endothelial barriers in the presence or absence of formyl-methionyl-leucyl-phenylalanine (fMLP). Rescue expression of ADAM15 in Adam15 Ϫ/Ϫ ECs restored neutrophil transendothelial migration. These data indicate that ADAM15 upregulation contributes to inflammatory lung injury by promoting endothelial hyperpermeability and neutrophil transmigration. vascular permeability; metalloproteinase; endothelial dysfunction; inflammation THE ADAMS (a disintegrin and metalloproteinase) are multifunctional transmembrane glycoproteins that are involved in a variety of biological processes (5, 17). In general, ADAMs are metalloproteinases that are capable of cleaving cell surface protein ectodomains and inducing signaling events through receptor shedding, and/or outside-in signaling (8,26). ADAM15 is a less studied ADAM isoform that is found in human vein endothelium (13) and is associated with certain types of cancer and chronic inflammatory or immunological disorders (5, 14, 21). In particular, ADAM15 supports cancer metastasis by promoting tumor cell migration and angiogenesis (21,24). Increased ADAM15 expression is also detected in atherosclerotic lesions, rheumatoid synovium, angiogenic retinas, and the intestines of patients with inflammatory bowl disease (1, 3-5). This suggests that increased ADAM15 expression is involved in a variety of inflammatory conditions.Our rec...

Novel regulators of endothelial barrier function

“…In contrast, leukocyte-expressed ADAM 10 but not ADAM 17 displays proinflammatory activities and may therefore serve as a target to limit inflammatory cell recruitment (114). Sun and colleagues (134) showed that ADAM 15 is activated during lung injury and disrupts endothelial barrier function and induces neutrophil infiltration. Therefore, LPS failed to induce inflammatory injury in ADAM 15 knockout mice.…”

Host transcriptional responses and SARS-CoV-2 isolates from the nasopharyngeal samples of Bangladeshi COVID-19 patients

“…Modulatory roles of integrins are well established in acute lung damages [70]. Similarly, aberrant expression of genes involved in integrin signaling can also provoke acute lung injuries, namely-ADAM15 [71], SDC1 [72], CD14 [73], CD47 [74], CD9 [75], HMGB1 [76], ITA6 [77], and ITAV [78] etc. Therefore, SARS-CoV-2 infection induced deregulation of these genes might be contributing towards the worsening of the normal pathobiology and functionality of lungs in COVID-19.…”

ADAM protein family – its role in tumorigenesis, mechanisms of chemoresistance and potential as diagnostic and prognostic factors

“…No major pathologies. Reduced neutrophil chemotactic transmigration across, attenuated pulmonary inflammatory response [177], faster development of osteoarthritis [178] ADAM17 Knock-out: Perinatal lethality [162], eyelid, hair, skin, lung development and heart valves defects [179,180]. Gene knock-down: eye, heart, skin defects, increased vulnerability to inflammation in DSS colitis [181].…”