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Is obstructive sleep apnea a cause of idiopathic pulmonary fibrosis?

To the Editor.--We read with pleasure Dr Leslie's thoughtful article describing a potential role for peripheral tractional lung injury in idiopathic pulmonary fibrosis (IPF). (1) Mechanical stretch is a well-known cause of acute lung injury during positive-pressure ventilation, (2) and the author makes a strong case for the role of alveolar stretch as a cause of alveolar injury in IPF. Notably missing from the paper, however, are postulated causes of tractional stress in the lung that could lead to IPF in susceptible individuals.

Work from our group (3) and others (4) suggests that obstructive sleep apnea (OSA) might be a cause of subclinical lung injury, as evidenced by elevated circulating markers of alveolar injury. In addition, animal work suggests that inspiratory resistive loading (similar obstructive hypopnea) can cause alveolar injury. (5) OSA is characterized by repetitive forced inspirations against a closed glottis (Muller maneuver) that are likely to cause major decreases in lung interstitial pressures, (6) resulting in alveolar deformation (7) and proinflammatory capillary responses, (8) including stress failure. (9) Such a pattern repeated multiple times each night for decades fits the hypothesis described by Dr Leslie. Indeed, OSA and IPF share similar demographic patterns, and OSA has been found to be prevalent in IPF. (10)

In addition to tractional injury, OSA could further injure the lung through oxidative stress (due to cyclic hypoxia-reoxygenation during recurrent apneas), through hypercapnic microRNA induction, (11) and perhaps through microaspiration due to gastroesophageal reflux (GER), a condition common to both IPF and OSA. Alternatively, the reported link between GER and IPF might be completely confounded by OSA.

Additional work is required to confirm that OSA is indeed a cause of alveolar injury in humans. An important step will be determining whether OSA treatment can slow or even reverse lung fibrosis in adults with IPF. Congratulations to Dr Leslie for developing a specific, detailed, and plausible hypothesis for the cause of this devastating and underinvestigated disease.


Department of Medicine

College of Physicians and Surgeons

Columbia University

New York, NY 10032

Department of Epidemiology

Mailman School of Public Health

Columbia University

New York, NY 10032




Department of Medicine

College of Physicians and Surgeons

Columbia University

New York, NY 10032


(1.) Leslie KO. Idiopathic pulmonary fibrosis may be a disease of recurrent, tractional injury to the periphery of the aging lung: a unifying hypothesis regarding etiology and pathogenesis. Arch Pathol Lab Med. 2011. Epub ahead of print. doi: 10.5858/ arpa.2011-0511-OA.

(2.) Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema: respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am Rev Respir Dis. 1988; 137(5):1159-1164.

(3.) Lederer DJ, Jelic S, Basner RC, Ishizaka A, Bhattacharya J. Circulating KL-6, a biomarker of lung injury, in obstructive sleep apnoea. Eur Respir J. 2009; 33(4):793-796.

(4.) Aihara K, Oga T, Harada Y, et al. Comparison of biomarkers of subclinical lung injury in obstructive sleep apnea. Respir Med. 2011; 105(6):939-945.

(5.) Toumpanakis D, Kastis GA, Zacharatos P, et al. Inspiratory resistive breathing induces acute lung injury. Am J Respir Crit Care Med. 2010;182(9): 1129-1136.

(6.) Glucksberg MR, Bhattacharya J. Effect of alveolar and pleural pressures on interstitial pressures in isolated dog lungs. J Appl Physiol. 1991; 70(2):914-918.

(7.) Perlman CE, Bhattacharya J. Alveolar expansion imaged by optical sectioning microscopy. J Appl Physiol. 2007;103(3):1037-1044.

(8.) Ichimura H, Parthasarathi K, Quadri S, Issekutz AC, Bhattacharya J. Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries. J Clin Invest. 2003; 111(5):691-699.

(9.) West JB, Mathieu-Costello O. Stress failure of pulmonary capillaries: role in lung and heart disease. Lancet. 1992; 340(8822):762-767.

(10.) Lancaster LH, Mason WR, Parnell JA, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest. 2009; 136(3):772-778.

(11.) Vohwinkel CU, Lecuona E, Sun H, et al. Elevated CO(2) levels cause mitochondrial dysfunction and impair cell proliferation. J Biol Chem. 2011; 286(43):37067-37076.

doi: 10.5858/arpa.2011-0650-LE

In Reply.--I am pleased to read the insightful and thought-provoking comments of Dr Lederer and colleagues regarding a credible role for obstructive sleep apnea (OSA) in the etiology and pathogenesis of idiopathic pulmonary fibrosis (IPF). The notion of recurrent stretch injury in this setting is appealing and potentially testable. As Dr Lederer knows all too well, there has been controversy in the literature regarding the incidence of OSA in IPF patients, although the actual data are a bit sparse and contradictory. (1-3)

I agree wholeheartedly with the comments of Dr Lederer and colleagues and I enthusiastically acknowledge my oversight. It would appear that great minds think alike. A friend and colleague, Steven Nathan, MD (medical director, Advanced Lung Disease & Transplant Program, Inova Fairfax Hospital, Fairfax, Virginia), had suggested this possibility to me a few months ago, emphasizing that OSA in IPF patients might be an interesting scenario for testing this hypothesis (written communication, September 2011). After copious revisions of the manuscript, I came to believe that I would serve the intent of the paper better by avoiding the proposal of potential avenues of investigation (eg, surfactant studies in IPF lung explants), preferring instead to offer those closest to the field the opportunity to bring their expertise to bear on the problem, unfettered by biases other than those related to the observed clinical, radiologic, and histopathologic expression of the disease.


Mayo Clinic Arizona

Scottsdale, AZ 85259

(1.) Lancaster LH, Mason WR, Parnell JA, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest. 2009; 136(3):772-778.

(2.) Mermigkis C, Chapman J, Golish J, et al. Sleep-related breathing disorders in patients with idiopathic pulmonary fibrosis. Lung. 2007; 185(3): 173-178.

(3.) Rasche K, Orth M. Sleep and breathing in idiopathic pulmonary fibrosis. J Physiol Pharmacol. 2009; 60(suppl 5): 13-14.

doi: 10.5858/arpa.2011-0685-LE
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Title Annotation:Letters to the Editor
Author:Lederer, David J.; Jelic, Sanja; Basner, Robert C.; Bhattacharya, Jahar
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:May 1, 2012
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