title: Recombinant osteopontin attenuates hyperoxia-induced acute lung injury through inhibiting nuclear factor kappa B and matrix metalloproteinases 2 and 9.
abstract: BACKGROUND
  Exposure of adult mice to more than 95% O2 produces a lethal injury by 72 hours. Nuclear factor kappa B (NF-κB) is a transcriptional factor that plays a key role in the modulation of cytokine networks during hyperoxia-induced acute lung injury (ALI). Osteopontin (OPN) is a phosphorylated glycoprotein produced principally by macrophages. Studies have reported that exogenous OPN can maintain the integrity of the cerebral microvascular basement membrane and reduce brain damage through inhibiting NF-κB activities in the brain after subarachnoid hemorrhage. However, it is not clear whether OPN can reduce lung injury during ALI by inhibiting transcriptional signal pathways of NF-κB and consequent inhibition of inflammatory cytokines. Thus we examined the effects and mechanisms of recombinant OPN (r-OPN) on ALI.
  
  
  METHODS
  Ninety-six mice were randomly divided into phosphate buffered saline (PBS) and r-OPN groups. Mice were put in an oxygen chamber (>95% O2) and assessed for lung injury at 24, 48, and 72 hours. Expressions of NF-κB, matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), and tissue inhibitors of MMP-2 and MMP-9 (TIMP-1, TIMP-2) mRNA in lungs were examined with RT-PCR. Expression and distribution of NF-κB protein in lungs were measured with immunohistochemistry.
  
  
  RESULTS
  Exposure to hyperoxia for 72 hours induced more severe lung injury in the PBS group compared with the r-OPN group. Expression of NF-κB mRNA in the PBS group exposed to hyperoxia for 48 and 72 hours was significantly higher than the r-OPN group (P < 0.05). With 72-hour exposure, expression of TIMP-1 mRNA in the r-OPN group was significantly higher than that of the PBS group (P < 0.05). Expression of TIMP-2 mRNA in the r-OPN group at 48 and 72 hours was significantly higher than those in the PBS group (P < 0.05). After 72-hour exposure, expression of NF-κB protein in airway epithelium in the PBS group was significantly higher than that in the r-OPN group (P < 0.05).
  
  
  CONCLUSIONS
  r-OPN can inhibit the release and activation of MMPs through inhibition of the expression of NF-κB and promotion of the expression of TIMPs, and alleviate hyperoxia-induced ALI.
authors.affiliation: Department of Respiratory Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China. Email: xfzh20008@163.com.
authors.forename: Xiangfeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Statistics, School of Public Health, Capital Medical University, Beijing 100069, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
authors.forename: Guangfa
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Respiratory Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
authors.forename: Zengzhi
authors.initials: Z
authors.lastname: Wang
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018496:Hyperoxia / Q000378:metabolism* / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9