Keratinocyte Growth Factor Enhances Post-Pneumonectomy Lung Growth by Alveolar Proliferation

Abstract

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.

Repairing Mechanisms for Distal Airway Injuries and Related Targeted Therapeutics for Chronic Lung Diseases

“…We could also induce the distal airway SSCs stemness by supplementing the essential stem cell growth factors and cytokines, whose availabilities are greatly reduced in chronic lung diseases. Exogeneous FGF7 (also known as keratinocyte growth factor) application could promote compensatory lung growth by alveolar proliferation post PNX in mice 108 . A randomized controlled phase-I clinic trial showed that intravenous application of FGF7 attenuated alveolar injury in patients with acute respiratory disease syndrome (ARDS) 109 .…”

Exploiting the potential of lung stem cells to develop pro-regenerative therapies

“…Lung epithelial regeneration has been improved in animal studies using both biopharmaceuticals and small molecule approaches. Biopharmaceutical approaches shown to increase epithelial cell proliferation after lung injury have included keratinocyte growth factor (KGF, Kaza et al, 2002 ; HGF, Dohi et al, 2000 ) and vascular endothelial growth factor (VEGF, Kunig et al, 2005 ). The small molecule LDN-193189 – a BMP antagonist – promoted basal cell proliferation during airway injury ( Tadokoro et al, 2016 ), while amlexanox – a Wnt-activator – was identified in a drug repurposing study and promoted repair in the elastase-induced emphysema mouse model ( Costa et al, 2021 ).…”