To a greater or lesser extent, all three isoforms of nitric oxide synthases (nNOS, iNOS, and eNOS) are expressed in the lung under both physiological and pathological conditions. Although the role of NOSs in lung diseases has been examined in pharmacological studies with non-selective NOSs inhibitors, it still remains to be fully elucidated due to non-specificity of the agents. We addressed this point in our mice lacking all three NOSs and in mouse lung disease models. Bleomycin treatment significantly increased pulmonary fibrosis, collagen content in the lung, and the total cell number in bronchoalveolar lavage fluid in wild-type (WT), single nNOS^-/-, iNOS^-/-, and eNOS^-/-, and triple n/i/eNOSs^-/- mice as compared with saline treatment. Those changes were significantly exacerbated only in the triple NOSs^-/- mice, but not in any single NOS^-/- mice, as compared with the WT mice, suggesting a protective role of NOSs in the development of pulmonary fibrosis（Respir Res 2014). Chronic hypoxic exposure significantly caused an increase in right ventricular pressure, right ventricular hypertrophy, and pulmonary artery remodeling in all the WT, single NOS^-/-, and triple NOSs^-/- mice as compared with normoxic exposure. Those alterations were significantly aggravated in the triple NOSs^-/- mice and, to a lesser extent, in the eNOS^-/- mice as compared with the WT mice, again suggesting a protective role of NOSs in the development of pulmonary hypertension (AJRCCM 2018). In contrast, ovalbumin-induced bronchial thickening, eosinophilic infiltration, and mucus secretion were markedly mitigated in the triple NOSs^-/- than in the WT mice, suggesting an opposing injurious role of NOSs in the development of bronchial asthma（Lung 2016). These results suggest that, even in the same lung organ, the role of NOSs appears to be different in distinct disease conditions, demonstrating diverse roles of NOSs in the pathogenesis of lung disorders.