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Leukocyte-Derived IL-10 Reduces Subepithelial Fibrosis Associated with Chronically Inhaled Endotoxin

Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina; and National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

Correspondence and requests for reprints should be addressed to Stavros Garantziotis, M.D., Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Box 3683, Durham, NC 27710. E-mail: garan001{at}mc.duke.edu

Endotoxin (LPS), a Gram-negative cell wall component, has potent proinflammatory properties. Acute LPS exposure causes airway inflammation; chronic exposure causes airway hyperreactivity and remodeling. IL-10 is an important antiinflammatory cytokine, which is decreased in patients with airway disease, such as asthma and cystic fibrosis. To examine the physiologic and therapeutic role of IL-10 in acute and chronic LPS-induced airway disease. Mice were exposed to aerosolized LPS once or daily for 4 wk. Endpoints were airway inflammation, airway reactivity to methacholine, extracellular matrix protein expression, and histologic analysis. IL-10–deficient mice developed significantly enhanced airway cellularity and remodeling when compared with C57BL/6 mice after chronic LPS inhalation. However they demonstrated less airway hyperreactivity associated with higher inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and lung lavage fluid nitrite levels. In a bone marrow transplantation model, the IL-10 antiinflammatory effect was dependent on the hematopoietic but not on the parenchymal IL-10 expression. Induced epithelial human IL-10 expression protected from the LPS effects and led to decreased collagen production. IL-10 attenuates chronic LPS-induced airway inflammation and remodeling. Physiologically, the antiinflammatory effect of IL-10 is mediated by hematopoietic cells. Therapeutically, adenovirus-driven expression of human IL-10 in airway epithelia is sufficient for its protective effect on inflammation and remodeling. The role of IL-10 on airway hyperreactivity is complex: IL-10 deficiency protects against LPS-induced hyperreactivity, and is associated with higher eNOS, iNOS, and airway nitrate levels.

Key Words: airway hyperreactivity • airway remodeling • endotoxin • IL-10

CLINICAL RELEVANCE This research elucidates the mechanism of chronic LPS-induced airway inflammation and remodeling and provides insights on the effect of IL-10. IL-10 is identified as a potential therapeutic agent for chronic LPS-induced airway inflammation and remodeling.

 

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