Intersectin‐1s: An Important Regulator of Cellular and Molecular Pathways in Lung Injury

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe syndromes resulting from the diffuse damage of the pulmonary parenchyma. ALI and ARDS are induced by a plethora of local or systemic insults, leading to the activation of multiple pathways responsible for injury, resolution, and repair or scarring of the lungs. Despite the large efforts aimed at exploring the roles of different pathways in humans and animal models and the great strides made in understanding the pathogenesis of ALI/ARDS, the only viable treatment options are still dependent on ventilator and cardiovascular support. Investigation of the pathophysiological mechanisms responsible for initiation and resolution or advancement toward lung scarring in ALI/ARDS animal models led to a better understanding of the disease's complexity and helped in elucidating the links between ALI and systemic multiorgan failure. Although animal models of ALI/ARDS have pointed out a variety of new ideas for study, there are still limited data regarding the initiating factors, the critical steps in the progression of the disease, and the central mechanisms dictating its resolution or progression to lung scarring. Recent studies link deficiency of intersectin-1s (ITSN-1s), a prosurvival protein of lung endothelial cells, to endothelial barrier dysfunction and pulmonary edema as well as to the repair/recovery from ALI. This review discusses the effects of ITSN-1s deficiency on pulmonary endothelium and its significance in the pathology of ALI/ARDS.

Endocytic deficiency induced by intersectin-1s knockdown alters the Smad2/3-Erk1/2 signaling balance downstream of Alk5

“…Acute lung injury (ALI) or mild acute respiratory distress syndrome (ARDS), according to the Berlin definition ( Ranieri et al, 2012 ), are associated with excessive apoptosis of endothelial and epithelial cells ( Henson and Tuder, 2008 ; Le et al, 2008 ; Predescu et al, 2013 ). Although apoptosis might induce pulmonary endothelial and epithelial barrier dysfunction leading to pulmonary edema, evidence suggests that apoptosis plays a beneficial role during ALI resolution owing to the pro-regenerative role of clearance of apoptotic cells ( Predescu et al, 2013 ; Schmidt and Tuder, 2010 ). This effect is mediated through the production of growth factors including TGFβ by macrophages engulfing apoptotic cells, or perhaps by other vascular cells ( Bardita et al, 2013 ; Henson and Tuder, 2008 ).…”

“…We have recently shown that in vivo deficiency of ITSN-1s, an isoform of ITSN-1 that is highly prevalent in lung endothelium and deficiency of which is relevant to the pathology of ALI/ARDS ( Bardita et al, 2013 ; Predescu et al, 2013 ), induces extensive lung endothelial cell apoptosis and injury; after only 7 days of ITSN knockdown (KD-ITSN), the remaining endothelial cells exhibited phenotypic changes including hyperproliferation and apoptosis resistance against ITSN-1s deficiency, leading to increased microvessel density, repair and remodeling of the injured lung. Under pathological conditions, dysfunctional endothelial cells also show altered intracellular trafficking and signaling of cell surface receptors, such as TGFβ-RI, which is implicated in the pathogenesis of ALI/ARDS ( Kranenburg et al, 2002 ; Morrell et al, 2001 ; Sehgal and Mukhopadhyay, 2007 ; Voelkel and Cool, 2003 ).…”

Intersectin-1s deficiency in pulmonary pathogenesis

“…Acute lung injury is associated with excessive apoptosis of pulmonary endothelial and epithelial cells, which induce endothelial and epithelial barrier dysfunction leading to pulmonary edema [ 67 , 68 ]. Acute lung injury is triggered by direct injury to the lung and can be secondary to other inflammatory conditions such as sepsis, pancreatitis or transfusion rejection.…”

“…Acute lung injury is triggered by direct injury to the lung and can be secondary to other inflammatory conditions such as sepsis, pancreatitis or transfusion rejection. Studies have shown that apoptotic pulmonary cells or macrophages engulfing apoptotic cells release substances such as growth factors, and create conditions that favor the emergence of apoptosis-resistant cells [ 68 , 69 ].…”

“…In acute lung injury, as in many pro-inflammatory states, full-length ITSN-1s expression is decreased [ 11 , 12 , 68 ]. ITSN-1s is important for the pro-survival signaling pathway mSos1/Ras/Erk1/2 MAPK which regulates cell survival, proliferation and vascular remodeling [ 6 , 9 , 10 ].…”