Effect of recombinant human keratinocyte growth factor in inducing Ras–Raf–Erk pathway-mediated cell proliferation in emphysematous mice lung

Abstract

Context: Pulmonary emphysema is resulted due to destruction of the structure of the alveoli. Recently, exogenous recombinant human Keratinocyte growth factor (rHuKGF) has been reported to induce the regeneration of gas exchange structures. However, the molecular mechanisms governing this process are so far unknown.

Objective: The objective of this study was to investigate the effect of rHuKGF in the lungs of emphysema-challenged mice on Ras–Raf–Erk (Erk, extracellular signal-regulated kinase) mediated signaling pathway that regulates alveolar epithelial cell proliferation.

Methods: Three experimental groups (i.e. emphysema, therapy and control group) were prepared. Lungs of mice were therapeutically treated at three occasions by oropharyngeal instillation of 10 mg rHuKGF per kg body weight after induction of emphysema by porcine pancreatic elastase (PPE). Subsequently, lung tissues from each mouse were collected for histopathology and molecular biology studies.

Results and discussion: Histopathology photomicrographs and Destructive Index analysis have shown that elastase induced airspace enlargement and loss of alveoli were recovered in therapy group. Moreover, proliferating cell nuclear antigen (PCNA) at mRNA and protein expression level was markedly increased in therapy group than emphysema group. Upon validation at mRNA level, expressions of FGF-7, FGF-R, Ras, c-Raf, Erk-1, Erk-2, c-Myc and were significantly increased, whereas Elk-1 was notably decreased in therapy group when compared with emphysema group and were well comparable with the control group.

Conclusion: Therapeutic supplementation of rHuKGF rectifies the deregulated Ras–Raf–Erk pathway in emphysema condition, resulting in alveolar epithelium regeneration. Hence, rHuKGF may prove to be a potential drug in the treatment of emphysema.

• Alveolar regeneration
• emphysema
• rHuKGF
• Ras–Raf–Erk pathway

Acknowledgements

The authors thank Rashid Ali (Institute of Nuclear Medicine and Allied Sciences, DRDO, New Delhi, India) for helping in handling of animals. The authors express sincere gratitude to Swedish Orphan Biovitrum (SOBI), Stockholm, Sweden, for providing rHuKGF. The authors confer special thanks to Dr. Vandana Muyal for critically reviewing this manuscript.