title: Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation.
abstract: Heme oxygenase-1 (HO-1) has been shown to display anti-inflammatory properties in models of acute pulmonary inflammation. For the first time, we investigated the role of leukocytic HO-1 using a model of HO-1(flox/flox) mice lacking leukocytic HO-1 that were subjected to lipopolysaccharide (LPS)-induced acute pulmonary inflammation. Immunohistology and flow cytometry demonstrated that activation of HO-1 using hemin decreased migration of polymorphonuclear leukocytes (PMNs) to the lung interstitium and bronchoalveolar lavage (BAL) in the wild-type and, surprisingly, also in HO-1(flox/flox) mice, emphasizing the anti-inflammatory potential of nonmyeloid HO-1. Nevertheless, hemin reduced the CXCL1, CXCL2/3, tumor necrosis factor-α (TNFα), and interleukin 6 (IL6) levels in both animal strains. Microvascular permeability was attenuated by hemin in wild-type and HO-1(flox/flox) mice, indicating a crucial role of non-myeloid HO-1 in endothelial integrity. The determination of the activity of HO-1 in mouse lungs revealed no compensatory increase in the HO-1(flox/flox) mice. Topical administration of hemin via inhalation reduced the dose required to attenuate PMN migration and microvascular permeability by a factor of 40, emphasizing its clinical potential. In addition, HO-1 stimulation was protective against pulmonary inflammation when initiated after the inflammatory stimulus. In conclusion, nonmyeloid HO-1 is crucial for the anti-inflammatory effect of this enzyme on PMN migration to different compartments of the lung and on microvascular permeability.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany.
authors.forename: F M
authors.initials: FM
authors.lastname: Konrad
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Knausberg
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Höne
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany.
authors.forename: K-C
authors.initials: KC
authors.lastname: Ngamsri
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Reutershan
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D054426:Chemokine CXCL2 / Q000235:genetics / Q000276:immunology; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D006427:Hemin / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C499706:CXCL2 protein, human; C499707:CXCL3 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D006427:Hemin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse