title: Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin.
abstract: 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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Box 3683, Durham, NC 27710, USA. garan001@mc.duke.edu
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
authors.forename: David M
authors.initials: DM
authors.lastname: Brass
authors.forename: Jordan
authors.initials: J
authors.lastname: Savov
authors.forename: John W
authors.initials: JW
authors.lastname: Hollingsworth
authors.forename: Erin
authors.initials: E
authors.lastname: McElvania-TeKippe
authors.forename: Katie
authors.initials: K
authors.lastname: Berman
authors.forename: Julia K L
authors.initials: JK
authors.lastname: Walker
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000256:Adenoviridae; D000280:Administration, Inhalation; D000818:Animals; D016026:Bone Marrow Transplantation; D016535:Bronchial Hyperreactivity / Q000378:metabolism; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002678:Chimera / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use; D007962:Leukocytes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D012333:RNA, Messenger / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D009573:Nitrites; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C440499:lipopolysaccharide, Escherichia coli O111 B4; D016753:Interleukin-10; D003094:Collagen; D019001:Nitric Oxide Synthase