Published ahead of print on June 29, 2006, doi:10.1165/rcmb.2006-0055OC Am. J. Respir. Cell Mol. Biol., Volume 35, Number 6, December 2006, 662-667 A more recent version of this article appeared on December 1, 2006
Submitted on February 4, 2006 Leukocyte-derived Interleukin-10 Reduces Subepithelial Fibrosis Associated with Chronically Inhaled EndotoxinStavros Garantziotis1*,1 Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA; National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 2 National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 3 Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA * To whom correspondence should be addressed. E-mail: garan001{at}mc.duke.edu.
Background: Endotoxin (lipopolysaccharide LPS), a gram-negative cell wall component, has potent pro-inflammatory properties. Acute LPS exposure causes airway inflammation; chronic exposure causes airway hyper-reactivity and remodeling. Interleukin-10 (IL-10) is an important anti-inflammatory cytokine, which is decreased in patients with airway disease such as asthma and cystic fibrosis. Objective: To examine the physiologic and therapeutic role of IL-10 in acute and chronic LPS-induced airway disease. Methods: Mice were exposed to aerosolized LPS once or daily for 4 weeks. Endpoints were airway inflammation, airway reactivity to methacholine, extracellular matrix protein expression, and histological analysis. Results: IL-10 deficient mice developed significantly enhanced airway cellularity and remodeling when compared to C57BL/6 mice following chronic LPS inhalation. However they demonstrated less airway hyper-reactivity associated with higher iNOS, eNOS and lung lavage fluid nitrite levels. In a bone marrow transplantation model, the IL-10 anti-inflammatory effect was dependent on the hematopoietic, but not on the parenchymal IL-10 expression. Induced epithelial hIL-10 expression protected from the LPS effects and led to decreased collagen production. Conclusions: IL-10 attenuates chronic LPS-induced airway inflammation and remodeling. Physiologically, the anti-inflammatory effect of IL-10 is mediated by hematopoietic cells. Therapeutically, adenoviral-driven expression of hIL-10 in airway epithelia is sufficient for its protective effect on inflammation and remodeling. The role of IL-10 on airway hyper-reactivity is complex: IL-10 deficiency protects against LPS-induced hyper-reactivity, and is associated with higher eNOS, iNOS and airway nitrate levels.
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