title: Inhibition of Acute Lung Injury by TNFR-Fc through Regulation of an Inflammation-Oxidative Stress Pathway.
abstract: BACKGROUND
  Acute lung injury (ALI), characterized by disruption of the lung alveolar-capillary membrane barrier and resultant pulmonary edema, and associated with a proteinaceous alveolar exudate, is a leading cause of morbidity and mortality. Currently, inflammation-oxidative stress interaction between TNF-α and NF-κB was identified as a key pathway of ALI. We hypothesized that a TNFR-Fc fusion protein would have beneficial effects in experimental ALI, and sought to test this idea in mice by blocking TNF-α.
  
  
  RESULTS
  Intratracheal instillation of lipopolysaccharide (LPS) into the lungs of ALI mice led to histiocyte apoptosis, and detection of serum and bronchoalveolar lavage fluid (BALF) cytokines, feedback between NF-κB and TNF-α, lung albumin leakage, lung damage, IκB kinase (IKK) and NF-κB activation, I-κB degradation, and oxidative injury. LPS administration raised pulmonary inflammation as reflected by increased inflammatory cytokines, alveoli protein concentration, and ALI scores. IKK is phosphorylated following LPS challenge, leading to I-κB degradation and NF-κB p65 phosphorylation. Furthermore, NF-κB is translocated into the nucleus and up-regulates TNF-α gene transcription. Infusion of TNFR-Fc 24h before LPS challenge significantly abrogated the increase of inflammatory cytokines, especially serum TNF-α concentration, as well as pulmonary alveoli protein levels, and diminished IKK and NF-κB activation and I-κB degradation. The nuclear translocation of NF-κB was inhibited, following by down-regulation of TNF-α gene transcription. In addition, LPS intratracheal instillation induced marked oxidative damage, such as a decrease in total anti-oxidation products and an increase in malondialdehyde (MDA), as well as up-regulation of oxidation enzymes. Histologic analysis and apoptosis scores revealed that the extent of tissue lesions was significantly reduced, but not abrogated, by TNF-α blockade.
  
  
  CONCLUSIONS
  Treatment with LPS alone increased inflammation and oxidative stress in ALI mice, while administration of TNFR-Fc 24h before LPS challenge broke the feedback between NF-κB and TNF-α, resulting in decreased pulmonary inflammation/oxidative damage and tissue destruction. These results suggest a potential role for TNF-α therapy to treat clinical ALI.
authors.affiliation: Department of Respiratory Medicine, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Weifeng
authors.affiliation: Department of Respiratory Medicine, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, Hospital No 458 of PLA, Guangzhou, Guangdong, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Yujie
authors.affiliation: Department of Respiratory Medicine, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Weifeng
authors.affiliation: MICU, Key Laboratory of Geriatric Infection and Organ Function Support of Guangdong Provincial, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Zhenhui
authors.affiliation: Department of Respiratory Medicine, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Wenjie
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology*; D000418:Albumins / Q000378:metabolism; D000818:Animals; D015824:Blood-Air Barrier / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D000068800:Etanercept / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D011654:Pulmonary Edema / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000418:Albumins; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D051550:I-kappa B Kinase; D000068800:Etanercept