title: DNaseI protects against Paraquat-induced acute lung injury and pulmonary fibrosis mediated by mitochondrial DNA.
abstract: BACKGROUND
  Paraquat (PQ) poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered.
  
  
  RESULTS
  We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF) were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated.
  
  
  CONCLUSIONS
  DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.
authors.affiliation: Department of Rheumatology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yuzhen
authors.affiliation: Department of Emergency Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yi
authors.affiliation: Department of Rheumatology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Xiaoxiang
authors.affiliation: Department of Emergency Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Emergency Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Changqing
authors.affiliation: Department of Rheumatology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Shuang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010269:Paraquat / Q000009:adverse effects*; D020011:Protective Agents / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D004272:DNA, Mitochondrial; D053583:Interleukin-1beta; D015850:Interleukin-6; D020011:Protective Agents; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D003850:Deoxyribonuclease I; D010269:Paraquat