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A5773 - Role of the Anti-Aging Hormone Klotho in Idiopathic Pulmonary Fibrosis
Author Block: J. W. Barnes1, D. Duncan1, D. Kurundkar1, S. Hutcheson1, N. J. Logsdon1, M. L. Locy1, S. Blumhof1, S. Helton1, G. King2, V. J. Thannickal1, S. Krick1; 1Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States, 2Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States.
Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that is associated with a poor prognosis. Several reports have demonstrated that cell senescence is one of the underlying mechanisms in the pathogenesis of IPF. Interestingly, α-klotho (Kl), an age-suppressing hormone, has been shown to be downregulated in chronic obstructive lung disease, and the lack of Kl causes airway cell apoptosis and oxidative stress. We have shown that lack of Kl is associated with increased inflammation in chronic airway diseases. However, the role of Kl in IPF has not been investigated.
Methods: Kl expression was assessed by quantitative real time PCR in lung tissue of bleomycin treated mice and in human primary fibroblasts of individuals with and without IPF. For in vitro experiments, lung fibroblasts were treated with human recombinant soluble Kl ± transforming growth factor beta (TGF-β) and expression levels of IL-6 and IL-8 were analyzed by PCR and ELISA. Furthermore, soluble Kl levels were examined in an age-matched IPF patient cohort and compared to healthy controls. Using an in vivo approach, adult wild-type (WT) and Kl overexpressing mice (Kl OE) were exposed to bleomycin via oropharyngeal instillation and lung fibrosis was determined by quantifying the hydroxyproline content of the lung.
Results: Kl mRNA levels were reduced in the bleomycin treated lung tissue of WT mice starting at day 3 and persisted until day 28. Consistent with this, circulating Kl was significantly reduced in IPF patient plasma and downregulated in isolated lung fibroblasts from IPF patients when compared to controls, respectively. Treatment with TGF-β caused a significant upregulation of IL-6 and 8 in human lung fibroblasts, which was inhibited by pre-incubation with recombinant human Kl. Finally, lung collagen content was augmented in the WT bleomycin-induced pulmonary fibrosis model, but significantly reduced in the Kl OE mice.
Conclusions: Downregulation of Klotho associates with an increase in age-associated markers, including those for chronic lung inflammation, in interstitial fibroblasts from IPF patients. In contrast, gain of Kl function attenuates bleomycin induced lung fibrosis in the in vivo mouse model. Taken together, these data suggest that the anti-aging hormone, Klotho, may target cell senescence and fibrosis, thus providing therapeutic approaches for IPF as well as other fibrotic diseases.