Abstract
Pulmonary fibrosis is a chronic and irreversible scarring disease in the lung with poor prognosis. Few therapies are available; therefore it is critical to identify new therapeutic targets. Our lab has previously identified the enzyme lactate dehydrogenase-A (LDHA) as a potential therapeutic target in pulmonary fibrosis. We found increases in LDHA protein and its metabolic product, lactate, in patients with idiopathic pulmonary fibrosis (IPF). Importantly, we described lactate as a novel pro-fibrotic mediator by acidifying the extracellular space, and activating latent transforming growth factor beta (TGF-β1) in a pH-dependent manner. We propose a pro-fibrotic feed-forward loop by which LDHA produces lactate, lactate decreases pH in the extracellular space and activates TGF-β1 which can further perpetuate fibrotic signaling. Our previous work also demonstrates that the LDHA inhibitor gossypol inhibits TGF-β1-induced myofibroblast differentiation and collagen production in vitro. Here, we employed a mouse model of bleomycin-induced pulmonary fibrosis to test whether gossypol inhibits pulmonary fibrosis in vivo. We found that gossypol dose-dependently inhibits bleomycin-induced collagen accumulation and TGF-β1 activation in mouse lungs when treatment is started on the same day as bleomycin administration. Importantly, gossypol was also effective at treating collagen accumulation when delayed 7 days following bleomycin. Our results demonstrate that inhibition of LDHA with the inhibitor gossypol is effective at both preventing and treating bleomycin-induced pulmonary fibrosis, and suggests that LDHA may be a potential therapeutic target for pulmonary fibrosis.
Highlights
Pulmonary fibrosis is a progressive, incurable interstitial lung disease
We have demonstrated that the enzyme responsible for the production of lactic acid, lactate dehydrogenase-A (LDHA), is elevated in lung tissue isolated from patients with idiopathic pulmonary fibrosis (IPF)
Lactate dehydrogenase-A is elevated in the lung tissue of mice exposed to bleomycin
Summary
Pulmonary fibrosis is a progressive, incurable interstitial lung disease. The median survival from the time of diagnosis is 2.9 years, though the prognosis varies substantially among individuals [1]. The increased expression of matrix proteins and enhanced contractile properties of myofibroblasts contribute to the progressive restrictive lung disease and diffusion impairment in patients with pulmonary fibrosis. Inhibition of these cellular processes may mitigate the progression of pulmonary fibrosis. In vitro overexpression of LDHA in primary human lung fibroblasts induces activation of TGFβ1 and myofibroblast differentiation [17]. We hypothesize that pharmacologic inhibition of LDHA via the LDH inhibitor, gossypol [19,20], will abrogate fibrotic changes in an in vivo model of bleomycin-induced pulmonary fibrosis. We demonstrate that gossypol is effective at inhibiting and treating bleomycin-induced pulmonary fibrosis
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