Abnormal lung phenotype in Rab38‐deficient rats, rodent models of Hermansky‐Pudlak syndrome

Abstract

Several Long Evans rat substrains carrying the phenotype of oculocutaneous albinism and bleeding diathesis are considered as rat model of the 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. We investigated the lung phenotype of Long Evans Cinnamon rats. The lung histology revealed uniform enlargement of distal airway space, and alveolar type II cells contained markedly enlarged lamellar bodies. Surfactant phosphatidylcholine (PC) and surfactant protein B were increased in the lung tissue and lamellar body fraction, but not in alveolar lumen. Surfactant protein A levels were decreased in the lung tissue and alveolar lumen. Isolated alveolar type II cells showed aberrant secretory pattern of newly synthesized [3H]PC, i.e. decreased basal secretion and remarkably amplified agonist‐induced secretion. We constructed recombinant adenovirus vector expressing Rab38. The agonist‐induced [3H]PC secretion in Rab38‐deficient cells infected with Ad‐Rab38 was decreased close to that in Rab38+/+ cells. Thus, Rab38‐deficient rats show alveolar structural deformity and aberrant lung surfactant homeostasis with altered alveolar type II cell morphology. These results suggest that Rab38 deficiency develops a complication of lung disease in the phenotype of HPS.