title: Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis.
abstract: BACKGROUND
  The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF.
  
  
  METHODS
  TRAIL(-/-) and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA.
  
  
  RESULTS
  TRAIL(-/-) mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19±0.8 wild type vs 11.5±5.4×10(4) TRAIL(-/-), p<0.0001), reduced neutrophil apoptosis (5.42±1.6% wild type vs 2.47±0.5% TRAIL(-/-), p=0.0003) and increased collagen (3.45±0.2 wild type vs 5.8±1.3 mg TRAIL(-/-), p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild-type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1±9.6 controls vs 32.3±7.2 pg/ml patients with IPF, p=0.002).
  
  
  CONCLUSIONS
  These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF.
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield, UK.
authors.forename: Emmet E
authors.initials: EE
authors.lastname: McGrath
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
authors.forename: Helen M
authors.initials: HM
authors.lastname: Marriott
authors.forename: Paul
authors.initials: P
authors.lastname: Mercer
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Nadine
authors.initials: N
authors.lastname: Arnold
authors.forename: Vanessa
authors.initials: V
authors.lastname: Singleton
authors.forename: Alfred A R
authors.initials: AA
authors.lastname: Thompson
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D018893:Bronchoalveolar Lavage; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D055370:Lung Injury / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D012129:Respiratory Function Tests; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency*
chemical_list: D015415:Biomarkers; D053221:TNF-Related Apoptosis-Inducing Ligand; D001761:Bleomycin; D003094:Collagen; D006909:Hydroxyproline