Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome

• Published in: American journal of physiology. Lung cellular and molecular physiology 2010-02, Vol.298 (2), p.L243-L251
• Main Authors: Osanai, Kazuhiro, Higuchi, Junko, Oikawa, Rieko, Kobayashi, Makoto, Tsuchihara, Katsuma, Iguchi, Masaharu, Huang, Jyongsu, Voelker, Dennis R, Toga, Hirohisa
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Genotype & phenotype; Hermanski-Pudlak Syndrome - pathology; Hermanski-Pudlak Syndrome - physiopathology; Humans; Liposomes - metabolism; Lung - cytology; Lung - metabolism; Lung - pathology; Lungs; Male; Mice; Mutation; Phenotype; Pulmonary Surfactants - metabolism; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Rats; Rats, Inbred LEC; Rats, Sprague-Dawley; Respiratory diseases; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00242.2009

1 Department of Respiratory Medicine, Kanazawa Medical University, Kahokugun, Ishikawa; and ; 2 Department of Human Pathology, Yamagata University Graduate School of Medicine, Yamagata, Yamagata, Japan; and ; 3 Program in Cell Biology, National Jewish Health, Denver, Colorado Submitted 23 July 2009 ; accepted in final form 29 October 2009 Several Long-Evans rat substrains carrying the phenotype of oculocutaneous albinism and bleeding diathesis are a rat model of Hermansky-Pudlak syndrome (HPS). The mutation responsible for the phenotype ( Ruby ) was identified as a point mutation in the initiation codon of Rab38 small GTPase that regulates intracellular vesicle transport. As patients with HPS often develop life-limiting interstitial pneumonia accompanied by abnormal morphology of alveolar type II cells, we investigated lung surfactant system in Long-Evans Cinnamon rats, one strain of the Ruby rats. The lungs showed conspicuous morphology of type II cells containing markedly enlarged lamellar bodies. Surfactant phosphatidylcholine and surfactant protein B were increased in lung tissues and lamellar bodies but not in alveolar lumen. Expression levels of mRNA for surfactant proteins A, B, C, and D were not altered. Isolated type II cells showed aberrant secretory pattern of newly synthesized [ 3 H]phosphatidylcholine, i.e., decreased basal secretion and remarkably amplified agonist-induced secretion. [ 3 H]phosphatidylcholine synthesis and uptake by type II cells were not altered. Thus Rab38-deficient type II cells appear to carry abnormality in lung surfactant secretion but not in synthesis or uptake. These results suggest that aberrant lung surfactant secretion may be involved in the pathogenesis of interstitial pneumonia in HPS. Ruby ; Long-Evans Cinnamon rat; alveolar type II cells; lamellar body Address for reprint requests and other correspondence: K. Osanai, Dept. of Respiratory Medicine, Kanazawa Medical Univ., 1-1 Uchinada-Daigaku, Kahokugun, Ishikawa 920-0293, Japan (e-mail: k-osanai{at}kanazawa-med.ac.jp ).