title: Macrophage migration inhibitory factor contributes to hypoxic pulmonary vasoconstriction in rats.
abstract: BACKGROUND
  Hypoxic pulmonary vasoconstriction may lead to pulmonary hypertension, but the underlying mechanisms of persistent vasoconstriction are still unclear. There is evidence that pulmonary inflammation contributes to the abnormalities of function in the pulmonary artery (PA) following chronic hypoxia exposure. Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine, and we found that expression of MIF was increased in the smooth muscle of PA from hypoxic pulmonary hypertensive rats. Therefore, the aim of the study was to investigate the role of MIF in modulating vasoreactivity of isolated PA rings.
  
  
  METHODS
  Sprague-Dawley rats were challenged by intermittent chronic hypoxia exposure for 4 weeks to establish hypoxic pulmonary hypertension models. Subsequently, immunohistochemistry and western blot assay were used to examine the MIF expression in pulmonary artery. Moreover, isometric force displacement was measured in isolated intrapulmonary artery.
  
  
  RESULTS
  In the isolated PA, our results showed that MIF mediated the enhanced pulmonary arterial vasoconstriction in response to chronic hypoxia, and the delayed hypoxic constriction in a biphasic pattern of constriction occurs in response to acute hypoxia. We also present the finding that MIF had no effect on force on its own, but concentration-dependently potentiated constrictions pre-evoked by phenylephrine under normoxic condition. The potentiation was independent of the endothelium. MIF-induced potentiation of phenylephrine-evoked constriction was partially inhibited by PKC inhibitor chelerythrine, p38 inhibitor SB 203580, ERK1/2 inhibitor U0126, respectively.
  
  
  CONCLUSIONS
  Our results suggested that MIF enhanced vasoconstriction of pulmonary artery elicited by agonist through PKC, p38 and ERK1/2 signal pathways, which may contributes to hypoxic pulmonary vasoconstriction.
authors: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, PR China.
authors: Bo
authors: B
authors: Zhang
authors: Ying
authors: Y
authors: Luo
authors: Man-Ling
authors: ML
authors: Liu
authors: Jing
authors: J
authors: Wang
authors: Dun-Quan
authors: DQ
authors: Xu
authors: Ming-Qing
authors: MQ
authors: Dong
authors: Yi
authors: Y
authors: Liu
authors: Min
authors: M
authors: Xu
authors: Hai-Ying
authors: HY
authors: Dong
authors: Peng-Tao
authors: PT
authors: Zhao
authors: Yu-Qi
authors: YQ
authors: Gao
authors: Zhi-Chao
authors: ZC
authors: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D014662:Vasoconstrictor Agents; D011493:Protein Kinase C; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C515599:Mif protein, rat