title: KGF-2 targets alveolar epithelia and capillary endothelia to reduce high altitude pulmonary oedema in rats.
abstract: High altitude pulmonary oedema (HAPE) severely affects non-acclimatized individuals and is characterized by alveolar flooding with protein-rich oedema as a consequence of blood-gas barrier disruption. Limited choice for prophylactic treatment warrants effective therapy against HAPE. Keratinocyte growth factor-2 (KGF-2) has shown efficiency in preventing alveolar epithelial cell DNA damages in vitro. In the current study, the effects of KGF-2 intratracheal instillation on mortality, lung liquid balance and lung histology were evaluated in our previously developed rat model of HAPE. We found that pre-treatment with KGF-2 (5 mg/kg) significantly decreased mortality, improved oxygenation and reduced lung wet-to-dry weight ratio by preventing alveolar-capillary barrier disruption demonstrated by histological examination and increasing alveolar fluid clearance up to 150%. In addition, KGF-2 significantly inhibited decrease of transendothelial permeability after exposure to hypoxia, accompanied by a 10-fold increase of Akt activity and inhibited apoptosis in human pulmonary microvascular endothelial cells, demonstrating attenuated endothelial apoptosis might contribute to reduction of endothelial permeability. These results showed the efficacy of KGF-2 on inhibition of endothelial cell apoptosis, preservation of alveolar-capillary barrier integrity and promotion of pulmonary oedema absorption in HAPE. Thus, KGF-2 may represent a potential drug candidate for the prevention of HAPE.
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: She
authors.forename: Arnaud
authors.initials: A
authors.lastname: Goolaerts
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Bi
authors.forename: Lin
authors.initials: L
authors.lastname: Tong
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Song
authors.forename: Chunxue
authors.initials: C
authors.lastname: Bai
mesh_terms: D000532:Altitude Sickness / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015824:Blood-Air Barrier; D002199:Capillary Permeability; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D020545:Respiratory Mucosa / Q000378:metabolism*
chemical_list: C496463:FGF10 protein, human; D051526:Fibroblast Growth Factor 10; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen