Inhalation of Stachybotrys chartarum Evokes Pulmonary Arterial Remodeling in Mice, Attenuated by Rho-Kinase Inhibitor |
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Authors: | Masaru Nagayoshi Yuji Tada James West Eri Ochiai Akira Watanabe Takahito Toyotome Nobuhiro Tanabe Yuichi Takiguchi Ayako Shigeta Tadashi Yasuda Kazutoshi Shibuya Katsuhiko Kamei Koichiro Tatsumi |
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Affiliation: | Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan. |
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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. |
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