title: Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses.
abstract: BACKGROUND
  Historically, fever, pneumonia, and sepsis after trauma are ascribed to pain and poor pulmonary toilet. No evidence supports that assertion however, and no known biologic mechanisms link injury to infection. Our studies show that injured tissues release mitochondria (MT). Mitochondrial damage-associated molecular patterns (mtDAMPs) however can mimic bacterial pathogen-associated danger molecules and attract neutrophils (PMN). We hypothesized that mtDAMPs from traumatized tissue divert neutrophils from the lung, causing susceptibility to infection.
  
  
  METHODS
  Anesthetized rats (6-10 per group) underwent pulmonary contusion (PC) by chest percussion. When modeling traumatic MT release, some rats had MT isolated from the liver (equal to 5% liver necrosis) injected intraperitoneally (IPMT). Negative controls had PC plus buffer intraperitoneally. Positive controls underwent PC plus cecal ligation and puncture. At 16 hours, bronchoalveolar and peritoneal lavages were performed. Bronchoalveolar lavage fluid (BALF) and peritoneal lavage fluid were assayed for PMN count, albumin, interleukin β, (IL-β), and CINC-1. Assays were normalized to blood urea nitrogen to calculate absolute concentrations.
  
  
  RESULTS
  PC caused alveolar IL-1β and CINC production and a 34-fold increase in BALF neutrophils. As expected, IPMT increased peritoneal IL-1β and CINC and attracted PMN to the abdomen. However, remarkably, IPMT after PC attenuated BALF cytokine accumulation and decreased BALF PMN. Cecal ligation and puncture had no direct effect on BALF PMNs but, like IPMT, blunted BALF leukocytosis after PC.
  
  
  CONCLUSIONS
  Rather than acting as a "second hit" to enhance PMN-mediated lung injury, mtDAMPs from trauma and pathogen-associated danger molecules from peritoneal infection diminish PMN accumulation in a contused lung. This may make the lung susceptible to pneumonia. This paradigm provides a novel mechanistic model of the relationship among blunt tissue trauma, systemic inflammation, and pneumonia that can be studied to improve trauma outcomes.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhao
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itagaki
authors.forename: Alok
authors.initials: A
authors.lastname: Gupta
authors.forename: Stephen
authors.initials: S
authors.lastname: Odom
authors.forename: Nicola
authors.initials: N
authors.lastname: Sandler
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Hauser
mesh_terms: D000007:Abdominal Injuries / Q000276:immunology* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D008168:Lung / Q000276:immunology*; D055370:Lung Injury / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D063306:Mitophagy / Q000276:immunology* / Q000502:physiology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010533:Peritoneal Lavage; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014949:Wounds, Nonpenetrating / Q000276:immunology* / Q000503:physiopathology
chemical_list: D018925:Chemokines; D016207:Cytokines
references.citation: J Trauma. 2007 Sep;63(3):596-600; discussion 600-2
references.pmid: 18073606
references.citation: Chest. 1994 Jan;105(1):224-8
references.pmid: 8275735
references.citation: Eur Respir J. 2001 Sep;18(3):522-9
references.pmid: 11589350
references.citation: Am Surg. 1999 Oct;65(10):987-90
references.pmid: 10515549
references.citation: Ann Surg. 1996 Nov;224(5):647-64
references.pmid: 8916880
references.citation: J Trauma. 2004 Oct;57(4):750-5
references.pmid: 15514528
references.citation: Shock. 2010 Jul;34(1):55-9
references.pmid: 19997055
references.citation: Science. 2010 Oct 15;330(6002):362-6
references.pmid: 20947763
references.citation: Arch Surg. 1991 Jan;126(1):97-9
references.pmid: 1985639
references.citation: Exp Mol Pathol. 1992 Feb;56(1):60-9
references.pmid: 1547869
references.citation: J Trauma. 1997 May;42(5):973-9
references.pmid: 9191684
references.citation: J Leukoc Biol. 1994 Nov;56(5):559-64
references.pmid: 7964163
references.citation: Respir Res. 2009 Sep 23;10:84
references.pmid: 19772669
references.citation: Am Surg. 2001 Feb;67(2):105-10
references.pmid: 11243529
references.citation: Injury. 2007 Dec;38(12):1336-45
references.pmid: 18048040
references.citation: Nature. 1993 Oct 14;365(6447):654-7
references.pmid: 8413628
references.citation: Biochem Biophys Res Commun. 1990 Mar 16;167(2):828-34
references.pmid: 2322255
references.citation: Am J Respir Cell Mol Biol. 1990 Apr;2(4):321-6
references.pmid: 2182081
references.citation: FASEB J. 1988 Feb;2(2):108-15
references.pmid: 3277884
references.citation: Am J Respir Crit Care Med. 2005 Apr 1;171(7):753-9
references.pmid: 15618463
references.citation: Ulus Travma Acil Cerrahi Derg. 2011 Jul;17(4):329-33
references.pmid: 21935831
references.citation: Acta Pathol Microbiol Immunol Scand C. 1987 Apr;95(2):47-54
references.pmid: 3037849
references.citation: Exp Mol Pathol. 1991 Aug;55(1):30-7
references.pmid: 1884768
references.citation: Langenbecks Arch Surg. 2005 Aug;390(4):333-41
references.pmid: 15995884
references.citation: Surgeon. 2006 Feb;4(1):23-31
references.pmid: 16459497
references.citation: Br J Anaesth. 2000 Jul;85(1):109-17
references.pmid: 10927999
references.citation: Infect Control Hosp Epidemiol. 2002 May;23(5):268-73
references.pmid: 12026152
references.citation: Crit Care Med. 2012 Sep;40(9):2631-7
references.pmid: 22732279
references.citation: Arch Surg. 2006 Nov;141(11):1132-40
references.pmid: 17116807
references.citation: Bioessays. 1999 Jan;21(1):17-28
references.pmid: 10070251
references.citation: J Trauma. 2010 Jun;68(6):1328-32; discussion 1332-4
references.pmid: 20539176
references.citation: Infect Immun. 1992 Apr;60(4):1268-72
references.pmid: 1548055
references.citation: Annu Rev Immunol. 2009;27:519-50
references.pmid: 19302047
references.citation: Nature. 2010 Mar 4;464(7285):104-7
references.pmid: 20203610
references.citation: Crit Care Med. 2013 Jan;41(1):159-70
references.pmid: 23222255
references.citation: Shock. 2005 Dec;24 Suppl 1:24-32
references.pmid: 16374369