Induction of Compensatory Lung Growth in Pulmonary Emphysema Improves Surgical Outcomes in Rats Running Head: HGF for Lung Volume Reduction Surgery

Rationale and Objectives Although lung volume reduction surgery (LVRS) has been widely employed as a therapeutic strategy for pulmonary emphysema, the procedure carries significant disadvantages, including significant operative mortality and a limited duration of effective response. Pulmonary resection is known to elicit compensatory growth in remnant lung tissues, however, it remains unclear whether and how compensatory growth occurs and contributes to clinical outcomes after LVRS. The goal of the present study was to characterize the role of hepatocyte growth factor (HGF) in compensatory lung growth following LVRS in a rat model of elastase-induced emphysema, since HGF is a potent pulmotrophic factor responsible for the regeneration of lung parenchyma in damaged lungs, including following a pulmonary resection. Methods and Main Results Unexpectedly, LVRS did not cause apparent increases in the endogenous HGF profiles of emphysematous lungs. Further, the lowered HGF production reflected a histologically inferior regenerative capacity in remnant lungs and was linked with impaired pulmonary functional recoveries after LVRS. When HGF was exogenously supplemented by gene transfection into emphysematous lungs simultaneously with LVRS, compensatory lung growth (as evidenced by increased lobe weight, and alveolar regeneration and angiogenesis) was significantly enhanced as compared with rats that underwent LVRS alone. Consequently, pulmonary function and gas exchange were also significantly improved. Conclusions We concluded that the induction of compensatory growth by growth factors following LVRS may be a new strategy to further improve clinical outcomes of LVRS in patients with pulmonary emphysema. (Word count: 239)