title: Inhalation of Stachybotrys chartarum evokes pulmonary arterial remodeling in mice, attenuated by Rho-kinase inhibitor.
abstract: Stachybotrys chartarum, a ubiquitous fungus in our environment, has been suspected of causing respiratory symptoms in humans, such as acute infant pulmonary hemorrhage and asthma. We previously established a mouse model in which repeated inhalation of Stachybotrys chartarum spores caused pulmonary hypertension. To further investigate the model, particularly in the pulmonary circulation, mice were intra-tracheally injected with spores, 18 times over 12 weeks. Severe muscularization was observed in the small- to medium-sized pulmonary arteries. Bronchoalveolar lavage fluid revealed an increase in eosinophils accompanied by high concentrations of Th2-associated cytokines, IL-4, IL-5, but not Th1-associated IFN-γ. The remodeling was temporary, resolving after cessation of spore inhalation. Chronic inhibition of the RhoA/Rho-kinase pathway by fasudil attenuated pulmonary arterial remodeling. These data suggest that Stachybotrys-mediated remodeling is caused by Th2-associated inflammation and can be resolved by Rho-kinase inhibition, either through direct effects on smooth muscle hypertrophy or through indirect effects on vascular inflammation. These data also show that extensive pulmonary vascular remodeling, often thought of as a fixed lesion, will spontaneously resolve in the absence of underlying molecular etiology.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Nagayoshi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Eri
authors.initials: E
authors.lastname: Ochiai
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Takahito
authors.initials: T
authors.lastname: Toyotome
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Ayako
authors.initials: A
authors.lastname: Shigeta
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yasuda
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shibuya
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kamei
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D008168:Lung / Q000382:microbiology* / Q000473:pathology*; D008172:Lung Diseases, Fungal / Q000382:microbiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012376:Rodent Diseases / Q000382:microbiology / Q000473:pathology; D013191:Stachybotrys / Q000472:pathogenicity*; D018418:Th2 Cells / Q000276:immunology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil