title: Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling.
abstract: BACKGROUND
  Both chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only chronic hypoxia appears to cause PH. We investigate the nature of the vascular remodeling and the expression and role of hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in explaining this differential response.
  
  
  METHODS
  We induced pulmonary vascular remodeling through either chronic hypoxia or antigen sensitization and challenge. Mice were evaluated for markers of PH and pulmonary vascular remodeling throughout the lung vascular bed as well as HIMF expression and genomic analysis of whole lung.
  
  
  RESULTS
  Chronic hypoxia increased both mean pulmonary artery pressure (mPAP) and right ventricular (RV) hypertrophy; these changes were associated with increased muscularization and thickening of small pulmonary vessels throughout the lung vascular bed. Allergic inflammation, by contrast, had minimal effect on mPAP and produced no RV hypertrophy. Only peribronchial vessels were significantly thickened, and vessels within the lung periphery did not become muscularized. Genomic analysis revealed that HIMF was the most consistently upregulated gene in the lungs following both chronic hypoxia and antigen challenge. HIMF was upregulated in the airway epithelial and inflammatory cells in both models, but only chronic hypoxia induced HIMF upregulation in vascular tissue.
  
  
  CONCLUSIONS
  The results show that pulmonary vascular remodeling in mice induced by chronic hypoxia or antigen challenge is associated with marked increases in HIMF expression. The lack of HIMF expression in the vasculature of the lung and no vascular remodeling in the peripheral resistance vessels of the lung is likely to account for the failure to develop PH in the allergic inflammation model.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Angelini
authors.forename: Qingning
authors.initials: Q
authors.lastname: Su
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamaji-Kegan
authors.forename: Chunling
authors.initials: C
authors.lastname: Fan
authors.forename: John T
authors.initials: JT
authors.lastname: Skinner
authors.forename: Andre
authors.initials: A
authors.lastname: Poloczek
authors.forename: Hazim
authors.initials: H
authors.lastname: El-Haddad
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.forename: Roger A
authors.initials: RA
authors.lastname: Johns
mesh_terms: D000818:Animals; D000941:Antigens; D062186:Arterial Pressure; D001230:Aspergillus / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D020869:Gene Expression Profiling; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D000860:Hypoxia / Q000150:complications*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000150:complications* / Q000276:immunology / Q000473:pathology; D011651:Pulmonary Artery / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000941:Antigens; D036341:Intercellular Signaling Peptides and Proteins; C413576:Retnla protein, mouse; D010047:Ovalbumin