title: Src tyrosine kinase inhibition prevents pulmonary ischemia-reperfusion-induced acute lung injury.
abstract: OBJECTIVE
  Pulmonary ischemia-reperfusion is a pathological process seen in several clinical conditions, including lung transplantation, cardiopulmonary bypass, resuscitation for circulatory arrest, atherosclerosis, and pulmonary embolism. A better understanding of its molecular mechanisms is very important.
  
  
  METHODS
  Rat left lung underwent in situ ischemia for 60 min, followed by 2 h of reperfusion. The gene expression profiles and Src protein tyrosine kinase (PTK) phosphorylation were studied over time, and PP2, an Src PTK inhibitor, was intravenously administered 10 min before lung ischemia to determine the role of Src PTK in lung injury.
  
  
  RESULTS
  Reperfusion following ischemia significantly changed the expression of 169 genes, with Mmp8, Mmp9, S100a9, and S100a8 being the most upregulated genes. Ischemia alone only affected expression of 9 genes in the lung. However, Src PTK phosphorylation (activation) was increased in the ischemic lung, mainly on the alveolar wall. Src PTK inhibitor pretreatment decreased phosphorylation of Src PTKs, total protein tyrosine phosphorylation, and STAT3 phosphorylation. It increased phosphorylation of the p85α subunit of PI3 kinase, a signal pathway that can inhibit coagulation and inflammation. PP2 reduced leukocyte infiltration in the lung, apoptotic cell death, fibrin deposition, and severity of acute lung injury after reperfusion. Src inhibition also significantly reduced CXCL1 (GRO/KI) and CCL2 (MCP-1) chemokine levels in the serum.
  
  
  CONCLUSIONS
  During pulmonary ischemia, Src PTK activation, rather than alteration in gene expression, may play a critical role in reperfusion-induced lung injury. Src PTK inhibition presents a new prophylactic treatment for pulmonary ischemia-reperfusion-induced acute lung injury.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, Toronto General Research Institute, Toronto, ON, Canada.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Oyaizu
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Fung
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiozaki
authors.forename: Zehong
authors.initials: Z
authors.lastname: Guan
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhang
authors.forename: Claudia C
authors.initials: CC
authors.lastname: dos Santos
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Marco
authors.initials: M
authors.lastname: Mura
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000517:prevention & control*; D000818:Animals; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D007511:Ischemia / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015424:Reperfusion / Q000009:adverse effects*; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D019061:src-Family Kinases