title: Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies.
abstract: Elevated soluble tumor necrosis factor-α receptor (sTNFR) levels in bronchoalveolar lavage fluid (BALF) are associated with poor patient outcome in acute lung injury (ALI). The mechanisms underlying these increases are unknown, but it is possible that pulmonary inflammation and increased alveolar epithelial permeability may individually contribute. We investigated mechanisms of elevated BALF sTNFRs in two in vivo mouse models of ALI. Anesthetized mice were challenged with intratracheal lipopolysaccharide or subjected to injurious mechanical ventilation. Lipopolysaccharide instillation produced acute intra-alveolar inflammation, but minimal alveolar epithelial permeability changes, with increased BALF sTNFR p75, but not p55. Increased p75 levels were markedly attenuated by alveolar macrophage depletion. In contrast, injurious ventilation induced substantial alveolar epithelial permeability, with increased BALF p75 and p55, which strongly correlated with total protein. BALF sTNFRs were not increased in isolated buffer-perfused lungs (devoid of circulating sTNFRs) subjected to injurious ventilation. These results suggest that lipopolysaccharide-induced intra-alveolar inflammation upregulates alveolar macrophage-mediated production of sTNFR p75, whereas enhanced alveolar epithelial permeability following mechanical ventilation leads to increased BALF p75 and p55 via plasma leakage. These data provide new insights into differential regulation of intra-alveolar sTNFR levels during ALI and may suggest sTNFRs as potential markers for evaluating the pathophysiology of ALI.
authors.affiliation: Section of Anaesthetics, Pain Medicine, and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Rd., London SW10 9NH, UK.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Dorr
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wilson
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Alicia C
authors.initials: AC
authors.lastname: Waite
authors.forename: Brijesh V
authors.initials: BV
authors.lastname: Patel
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Kieran P
authors.initials: KP
authors.lastname: O'Dea
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology; D008070:Lipopolysaccharides; D016676:Macrophages, Alveolar / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000209:etiology / Q000276:immunology*; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D012121:Respiration, Artificial / Q000009:adverse effects; D013997:Time Factors; D015854:Up-Regulation; D055397:Ventilator-Induced Lung Injury / Q000209:etiology / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; C440499:lipopolysaccharide, Escherichia coli O111 B4