Endothelial Cell ICAM-1 And SHP-2 Interaction In Acute Lung Injury

Acute lung injury(ALI)is characterized by impared microvascular endothelial cell and alveolar epithelial cell,an increased permeability of alveolar-capillary,lung edema with protein-rich fluid,ALI would develop into acute respiratory distress syndrome(ARDS).The main functional molecules vessel endothelial cadherin of endothelial plays an important role in inflammation.Endothelial surface Intercellular adhesion molecule-1(ICAM-1)mediates leukocytes firm adhesion and initiates subsequent trans-endothelial migration.Endothelial adhesion molecule VE-cadherin is the main component of endothelial adhesion,regulating endothelial permeability and controlling leukocyte transmigration.The molecular transit from ICAM-1 mediated firm adhesion to VE-cadherin mediated transmigration remains elusive.In this report the role of Src homology domain 2(SH2)-containing phos-phatase-2(SHP-2)during this transmit was determined.First ICAM-1 is able to form immunoprecipitated complex with SHP-2,downregulation of SHP-2 with the silencing siRNA in endothelial cells results in higher basal Src activity and decrease of the ICAM-1 activation induced Src activation.In addition,downregulation of SHP-2 also increases neutrophil endothelial adhesion,but inhibits neutrophil transmigration.Immunoprecipitation further revealed that VE-cadherin and its associated ?-catenin are also able to form immuno-complex with both ICAM-1 and SHP-2.While activation of ICAM-1 induces the dissociation of VE-cadherin from ICAM-1,downregulation of SHP-2 greatly prevents the association of ICAM-1 with VE-cadherin.Furthermore,downregulation of SHP-2 in vivo promotes more LPS induced neutrophil recruitment in the mouse lungs,but with less and delayed neutrophil extravasion.These results suggest that SHP-2 is able to modulate the ICAM-1 association with VE-cadherin and regulating neutrophil adhesion and transmigration.Our study will provide a new method to prevent acute lung injury.