Recombinant Human Keratinocyte Growth Factor Induces Akt Mediated Cell Survival Progression in Emphysematous Mice.
Emphysema has been associated with decreased VEGF and VEGFR-2 expression and the presence of high numbers of apoptotic alveolar cells. Keratinocyte growth factor stimulates VEGF synthesis which in turn confers normal lung structure maintenance via the Akt pathway. In this study the potential role of rHuKGF in the improvement of deregulated Akt mediated cell survival pathway in emphysematous mice was investigated.
Three experimental groups, i.e., emphysema, treatment and control groups, were prepared. Lungs of mice were treated on 3 occasions by oropharyngeal instillation of 10mg rHuKGF per kg body weight after induction of emphysema with porcine pancreatic elastase. Subsequently, lung tissues from mice were collected for histopathology and molecular biology studies.
Histopathology photomicrographs and destructive index analysis have shown that elastase-induced airspace enlargement and loss of alveoli recovered in the treatment group. rHuKGF stimulates VEGF production which in turn induces the Akt mediated cell survival pathway in emphysematous lungs. mRNA expression of VEGF, VEGFR, PI3K and Akt was significantly increased while Pten, Caspase-9 and Bad was notably decreased in treatment group when compared with emphysema group, being comparable with the control group. Moreover, VEGF protein expression was in accordance with that found for mRNA.
Therapeutic rHuKGF supplementation improves the deregulated Akt pathway in emphysema, resulting in alveolar cell survival through activation of the endogenous VEGF-dependent cell survival pathway. Hence rHuKGF may prove to be a potential drug in the treatment of emphysema.
Prakash Muyal J
，Kumar D
，Kotnala S
，Muyal V
，Kumar Tyagi A
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rHuKGF ameliorates protease/anti-protease imbalance in emphysematous mice.
We attempted to elucidate the beneficial role of rHuKGF supplementation in the amelioration of protease/antiprotease imbalance and TGF-β1 signaling pathway leading to alveolar tissue maintenance in elastase induced emphysematous mice. Thirty two male C57BL mice were divided into four groups i.e. control, emphysema, therapy and rHuKGF only and were oropharyngeally instilled with saline/porcine pancreatic elastase/rHuKGF. Subsequently, lungs from mice were collected for histopathology and molecular biology studies. rHuKGF supplementation significantly ameliorated the mRNA expressions of CRP, TNF-α, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, A1AT, TIMP1, TIMP2, PCNA, Ki67, SPB, SPC and PdPn. MMP-2 and TIMP-1 enzyme activity was resolved due to rHuKGF. Likewise, due to rHuKGF supplementation the protein expressions of CRP, MMP2, MMP7, MMP8 & CTSE, SERPINE1, SERPINA1, TIMP4, GSTA1, HDAC3, PCNA, CDH1, SP-B & SP-C were ameliorated. Moreover, the mRNA expressions of overall TGFβ-1 pathway was also significantly ameliorated due to rHuKGF supplementation. Lung histopathology represents recovery of lost alveolar septa due to rHuKGF supplementation. Moreover, positive DAB staining of PCNA, SP-B & SP-C was observed due to rHuKGF supplementation at tissue level. rHuKGF is therapeutically potent in maintaining pulmonary tissue integrity by amelioration of protease/antiprotease imbalance and TGFβ-1 pathway in emphysema.
Kotnala S
，Tyagi A
，Muyal JP
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