Pneumonectomy results in rapid compensatory growth of the remaining lung and also leads to increased flow and shear stress, which are known to stimulate endothelial nitric oxide synthase (eNOS). Nitric oxide is an essential mediator of vascular endothelial growth factor-induced angiogenesis, which should necessarily occur during compensatory lung growth. Thus our hypothesis is that eNOS is critical for compensatory lung growth. To test this, left pneumonectomy was performed in eNOS-deficient mice (eNOS−/−), and compensatory growth of the right lung was characterized throughout 14 days postpneumonectomy and compared with wild-type pneumonectomy and sham controls. Compensatory lung growth was severely impaired in eNOS−/− mice, as demonstrated by significant reductions in lung weight index, lung volume index, and volume of respiratory region. Also, pneumonectomy-induced increases in alveolar surface density and cell proliferation were prevented in eNOS−/− mice, indicating that eNOS plays a role in alveolar hyperplasia. Compensatory lung growth was also impaired in wild-type mice treated with the nitric oxide synthase inhibitor N G-nitro-l-arginine methyl ester. Together, these results indicate that eNOS is critical for compensatory lung growth.
Background Keratinocyte growth factor (KGF) has been shown to play an important role in pneumocyte proliferation and lung development. We hypothesized that exogenous KGF would enhance postpneumonectomy compensatory lung growth through alveolar proliferation. Methods and Results Adult Sprague–Dawley rats were used. Left pneumonectomy was performed in group P, sham thoracotomy in group S, and left pneumonectomy with administration of KGF (6.25 mg/week, intraperitoneally) in group PK. Lung weight index (LWI), lung volume index (LVI), and alveolar cell proliferation index (CPI) were measured in the right lung at 10 and 21 days after surgery. Morphometric analysis was used to determine alveolar surface density (Sv) and total volume of respiratory region (TVvr). As expected, LWI, LVI, and CPI were significantly increased after pneumonectomy at both time points in group P. The administration of KGF resulted in further significant enhancements of LWI, LVI, and CPI in group PK. TVvr was significantly increased in group P and further enhanced in group PK. Interestingly, Sv was not altered in group P but was significantly elevated in group PK. Administration of KGF to sham-operated animals did not alter LWI, LVI, or CPI. Conclusions KGF enhances compensatory lung growth after pneumonectomy in adult rats as indicated by increased LWI, LVI, and CPI. KGF induces new alveolar formation, as indicated by increases in Sv and TVvr. We believe that this is the first evidence that KGF can induce new alveolar formation in mature lungs.
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