Reply: From Idiopathic Pulmonary Fibrosis to Cystic Fibrosis: Got Lactate?

Abstract

From the Authors: We thank Worlitzsch and colleagues for their thoughtful response and are pleased that they read our article with such enthusiasm. We echo their thoughts on the potential pathogenic role of lactic acid in lung disease. In our article, we described the impact of lactate on fibroblasts, notably its induction of myofibroblast differentiation via pH-dependent activation of transforming growth factor (TGF)-β (1). Although we demonstrated that fibroblasts produce excess lactic acid in the presence of TGF-β and that fibroblasts obtained from patients with idiopathic pulmonary fibrosis (IPF) produced more lactic acid than normal fibroblasts, we do acknowledge that fibroblasts are not the only cells in the lung responsible for the generation of lactic acid. Neutrophils, although present in the lung tissue of patients with IPF, are not abundant, and therefore, at least in the case of IPF, are less likely to be the predominant source of lactic acid. We suspect that the epithelium, particularly damaged epithelium in areas of fibrosis, may also be a source of lactic acid. Regardless of the cell type of origin, we anticipate that lactic acid may eventually be shown to be part of the pathogenesis of a variety of lung diseases, including cystic fibrosis (CF) and IPF. The current paradigm proposed for the initiation of pulmonary fibrosis includes an insult to the epithelium, a subsequent aberrant subepithelial fibroblast cellular response resulting in exaggerated scar formation, and an inability of the epithelial cells to restore a functional barrier (2). Worlitzsch and colleagues’ response to our article detailing their experience with lactic acid release by neutrophils raises important questions regarding the role of lactic acid in the development of lung disease. First, is lactic acid an important component of normal wound healing in the lung and elsewhere? There are reports of elevated lactic acid concentrations in skin wounds that are associated with the normal, healthy healing response to dermal injury (3). The normal wound healing response in the lung is less well characterized but likely involves many cell types, including neutrophils, epithelial cells, and/or fibroblasts. The exact role of each cell type in the wound healing response is still being investigated. One potentially important mechanism in wound repair is the cross talk between fibroblasts and neutrophils. Ling and colleagues demonstrated that fibroblasts enhance the proinflammatory properties of neutrophils and promote neutrophil survival (4). This raises the possibility of a potential prohomeostatic mechanism for the promotion of wound healing. Neutrophil influx in damaged lung tissue could result in an increase in lactic acid and a decrease in the extracellular pH. This in turn could result in a pro–wound-healing milieu. The decrease in pH could directly create a hostile environment for microbial organisms, and the activation of TGF-β and induction of myofibroblast differentiation could promote wound contracture and enhance neutrophil activity. Although neutrophils are not abundant in IPF lung tissue, they may be important in the initiation of the disease and may certainly play a more central role in CF. Second, if lactic acid is part of a normal wound-healing process, what factors lead to its excess production and how can this process be mitigated? In skin wound healing, lactic acid concentrations exceeding the 10 to 15 mM range have been shown to be associated with poor wound healing (5). Therefore, we hypothesize that an important problem in both CF and IPF is not the mere elevation of lactate, but the degree of elevation. Equally important are the cell type(s) responsible for the generation of lactic acid and the resulting local tissue concentrations of lactic acid. For CF, this may be the characteristic neutrophil infiltrates. For IPF, we suspect that fibroblasts and epithelial cells may be responsible. The exact mechanisms regulating each cell type and its metabolic contribution to lactic acid production and/or lung disease require additional investigation.