We read the contribution of Kottmann and coworkers on the role of lactic acid in idiopathic pulmonary fibrosis (IPF) (1) with great interest. The authors showed ...
Correspondence Lactate Levels in Airways of Patients with Cystic Fibrosis and Idiopathic Pulmonary Fibrosis To the Editor:
We read the contribution of Kottmann and coworkers on the role of lactic acid in idiopathic pulmonary fibrosis (IPF) (1) with great interest. The authors showed that lactic acid is elevated in the lung tissue of patients with IPF and proposed that lactic acid induced myofibroblast differentiation via activation of transforming growth factor-b with a subsequent increase of hypoxiainducible factor-1a and lactate dehydrogenase-5 expression (1). The source of lactate, however, was not identified. Our investigations on lactate expression in sputum and bronchoalveolar lavage (BAL) samples from patients with the hereditary disease cystic fibrosis (CF) suggest a potential source. It is generally accepted that neutrophils are a predominant cell type in lung tissues and airways of patients with CF and IPF (2, 3), although neutrophil influx is more intense in CF (4), and the mechanisms that lead to neutrophil influx are obviously different. Activation of neutrophils with subsequent necrotic decay during chronic stimulation provokes the release of various components from neutrophil granules and cytosol, and large amounts of lactate can be present in airspace secretions (5). Disrupted microvasculature and impaired angiogenesis may promote tissue ischemia in IPF (6), and tissue ischemia has also been observed in fibrotic tissues in systemic sclerosis (7). Our data show concentrations of lactate in sputum (3.4 6 2.3 mmol/L) that are similar to that measured by Kottmann and coworkers (3.8 6 0.5 mmol/L) (1), and we have demonstrated profoundly hypoxic conditions in airspace secretions of patients with CF via bronchoscopy (8). Additionally, lactate can be detected in BAL from patients with CF (unpublished data) and correlates with neutrophil influx and concentrations of neutrophil granule contents (myeloperoxidase and elastase). Strikingly, as in IPF, chronic inflammation in CF leads to alveolar tissue remodeling with extensive expression of nuclear factor-kB, insulin-like growth factor-1, intercellular adhesion molecule-1, and increased numbers of myofibroblasts (2). Thus, accumulation of lactate, which may be derived from neutrophils under conditions of tissue hypoxia, may promote pathophysiological mechanisms of tissue remodeling in CF that are similar to that described by Kottmann and colleagues in IPF. Author disclosures are available with the text of this letter at www.atsjournals.org.
Dieter Worlitzsch, M.D., Ph.D. University Hospital of Halle-Wittenberg Halle, Germany Keith C. Meyer, M.M., M.S. University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Gerd Döring, Ph.D. University Hospital Tuebingen Tuebingen, Germany References 1. Kottmann RM, Kulkarni AA, Smolnycki KA, Lyda E, Dahanayake T, Salibi R, Honnons S, Jones C, Isern NG, Hu JZ, et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-b. Am J Respir Crit Care Med 2012;186:740–751.
2. Ulrich M, Worlitzsch D, Viglio S, Siegmann N, Iadarola P, Shute JK, Geiser M, Pier GB, Friedel G, Barr ML, et al. Alveolar inflammation in cystic fibrosis. J Cyst Fibros 2010;9:217–227. 3. Hunninghake GW, Gadek JE, Lawley TJ, Crystal RG. Mechanisms of neutrophil accumulation in the lungs of patients with idiopathic pulmonary fibrosis. J Clin Invest 1981;68:259–269. 4. Meyer KC, Lewandoski JR, Zimmerman JJ, Nunley D, Calhoun WJ, doPico GA. Human neutrophil elastase and elastase/ 1-antiprotease complex in cystic fibrosis: comparison to interstitial lung disease and evaluation of the effect of intravenous antibiotic therapy. Am Rev Respir Dis 1991;144:580–585. 5. Bensel T, Stotz M, Borneff-Lipp M, Wollschläger B, Wienke A, Taccetti G, Campana S, Meyer KC, Jensen PØ, Lechner U, et al. Lactate in cystic fibrosis sputum. J Cyst Fibros 2011;10:37–44. 6. Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, Worthen GS. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med 2004;170:242–251. 7. Manetti M, Guiducci S, Ibba-Manneschi L, Matucci-Cerinic M. Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis. J Cell Mol Med 2010;14:1241–1254. 8. Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer P, Bellon G, Berger J, Weiß T, et al. Effects of reduced oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 2002;109:317–325. Copyright ª 2013 by the American Thoracic Society
Reply: From Idiopathic Pulmonary Fibrosis to Cystic Fibrosis: Got Lactate? 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)-b (1). Although we demonstrated that fibroblasts produce excess lactic acid in the presence of TGF-b 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
