{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T11:13:15Z","timestamp":1793445195225,"version":"4.5.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2012,10,1]],"date-time":"2012-10-01T00:00:00Z","timestamp":1349049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-\u03b2 activation in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; \u03b1-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-\u03b2. TGF-\u03b2 induced expression of LDH5 via hypoxia-inducible factor 1\u03b1 (HIF1\u03b1). Importantly, overexpression of both HIF1\u03b1 and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-\u03b2 to induce differentiation. Furthermore, inhibition of both HIF1\u03b1 and LDH5 inhibited TGF-\u03b2\u2013induced myofibroblast differentiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-\u03b2. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201201-0084oc","type":"journal-article","created":{"date-parts":[[2012,8,24]],"date-time":"2012-08-24T00:30:34Z","timestamp":1345768234000},"page":"740-751","source":"Crossref","is-referenced-by-count":400,"title":["Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-\u03b2"],"prefix":"10.1093","volume":"186","author":[{"given":"Robert Matthew","family":"Kottmann","sequence":"first","affiliation":[{"name":"Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit A.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of 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