title: TLR4 is a negative regulator in noninfectious lung inflammation.
abstract: Low m.w. hyaluronan (LMW HA) has been shown to elicit the expression of proinflammatory cytokines and chemokines in various cells in vitro. However, the effects of this molecule in vivo are unknown. In this study, we report that intratracheal administration of LMW HA (200 kDa) causes inflammation in mouse lung. A lack of TLR4 is associated with even stronger inflammatory response in the lung as shown by increased neutrophil counts and elevated cytokine and chemokine concentrations. We also demonstrate that TLR4 anti-inflammatory signaling is dependent upon a MyD88-independent pathway. TLR4-mediated IL-1R antagonist production plays a negative regulatory role in LMW HA (200 kDa) induced lung inflammation. These data provide a molecular level explanation for the function of TLR4 in LMW HA (200 kDa)-induced lung inflammation, as inhibition of the beta form of pro-IL-1 promotes an anti-inflammatory response.
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. hzhao5@partners.org
authors.forename: Hang
authors.initials: H
authors.lastname: Zhao
authors.forename: Shaw-Wei
authors.initials: SW
authors.lastname: Leu
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
authors.forename: Rejmon
authors.initials: R
authors.lastname: Dedaj
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Zhao
authors.forename: Hari G
authors.initials: HG
authors.lastname: Garg
authors.forename: Lianjun
authors.initials: L
authors.lastname: Shen
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Aviva
authors.initials: A
authors.lastname: Shiedlin
authors.forename: Huahao
authors.initials: H
authors.lastname: Shen
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Quinn
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hales
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002463:Cell Membrane Permeability / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000502:physiology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008970:Molecular Weight; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid