Abstract
BackgroundIdiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment.MethodsAEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments.ResultsAEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs.ConclusionsThese results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease, characterized by progressive and extensive formation of fibrous tissue in the pulmonary parenchyma
Numerous gene-related changes found in Idiopathic Pulmonary Fibrosis (IPF), including mTOR activation and miR200 family downregulation, are known to increase expression of the lactate dehydrogenase (LDH)-A subunit which drives lactic acid production, and LDHA activity has been proposed as a target for IPF therapy [13, 15,16,17]
As presented in this report, we examined and compared metabolic profiles of Alveolar type II epithelial cells (AEC2) isolated from IPF and nonfibrotic patient explant lung tissues to test the hypothesis that lactate metabolism is altered in IPF AEC2s
Summary
Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease, characterized by progressive and extensive formation of fibrous tissue in the pulmonary parenchyma. Fibroblasts have been the focus of IPF progression studies [6, 7]; alveolar type II epithelial cells (AEC2) are gaining recognition as playing important roles in exacerbating the damage that promotes the disease [8, 9]. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment
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