title: Complement inhibition alleviates paraquat-induced acute lung injury.
abstract: The widely used herbicide, paraquat (PQ), is highly toxic and claims thousands of lives from both accidental and voluntary ingestion. The pathological mechanisms of PQ poisoning-induced acute lung injury (ALI) are not well understood, and the role of complement in PQ-induced ALI has not been elucidated. We developed and characterized a mouse model of PQ-induced ALI and studied the role of complement in the pathogenesis of PQ poisoning. Intraperitoneal administration of PQ caused dose- and time-dependent lung damage and mortality, with associated inflammatory response. Within 24 hours of PQ-induced ALI, there was significantly increased expression of the complement proteins, C1q and C3, in the lung. Expression of the anaphylatoxin receptors, C3aR and C5aR, was also increased. Compared with wild-type mice, C3-deficient mice survived significantly longer and displayed significantly reduced lung inflammation and pathology after PQ treatment. Similar reductions in PQ-induced inflammation, pathology, and mortality were recorded in mice treated with the C3 inhibitors, CR2-Crry, and alternative pathway specific CR2-fH. A similar therapeutic effect was also observed by treatment with either C3a receptor antagonist or a blocking C5a receptor monoclonal antibody. Together, these studies indicate that PQ-induced ALI is mediated through receptor signaling by the C3a and C5a complement activation products that are generated via the alternative complement pathway, and that complement inhibition may be an effective clinical intervention for postexposure treatment of PQ-induced ALI.
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
authors.forename: Shihui
authors.initials: S
authors.lastname: Sun
authors.forename: Hanbin
authors.initials: H
authors.lastname: Wang
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhao
authors.forename: Yingbo
authors.initials: Y
authors.lastname: An
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Lanying
authors.initials: L
authors.lastname: Du
authors.forename: Hongbin
authors.initials: H
authors.lastname: Song
authors.forename: Fei
authors.initials: F
authors.lastname: Qiao
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wu
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Yusen
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003167:Complement Activation / Q000187:drug effects* / Q000235:genetics; D015922:Complement C1q / Q000378:metabolism; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010269:Paraquat; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000378:metabolism; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; C527099:CR2-Crry fusion protein, mouse; D003176:Complement C3; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011993:Recombinant Fusion Proteins; C085567:complement C3a receptor; D015922:Complement C1q; D010269:Paraquat