title: Cecal ligation and puncture followed by methicillin-resistant Staphylococcus aureus pneumonia increases mortality in mice and blunts production of local and systemic cytokines.
abstract: Mortality in the intensive care unit frequently results from the synergistic effect of two temporally distinct infections. This study examined the pathophysiology of a new model of intra-abdominal sepsis followed by methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Mice underwent cecal ligation and puncture (CLP) or sham laparotomy followed 3 days later by an intratracheal injection of MRSA or saline. Both CLP/saline and sham/MRSA mice had 100% survival, whereas animals with CLP followed by MRSA pneumonia had 67% 7-day survival. Animals subjected to CLP/MRSA had increased bronchoalveolar lavage concentrations of MRSA compared with sham/MRSA animals. Animals subjected to sham/MRSA pneumonia had increased bronchoalveolar lavage levels of interleukin 6 (IL-6), tumor necrosis factor α, and granulocyte colony-stimulating factor compared with those given intratracheal saline, whereas CLP/MRSA mice had a blunted local inflammatory response with markedly decreased cytokine levels. Similarly, animals subjected to CLP/saline had increased peritoneal lavage levels of IL-6 and IL-1β compared with those subjected to sham laparotomy, whereas this response was blunted in CLP/MRSA mice. Systemic cytokines were upregulated in both CLP/saline and sham/MRSA mice, and this was blunted by the combination of CLP/MRSA. In contrast, no synergistic effect on pneumonia severity, white blood cell count, or lymphocyte apoptosis was identified in CLP/MRSA mice compared with animals with either insult in isolation. These results indicate that a clinically relevant model of CLP followed by MRSA pneumonia causes higher mortality than could have been predicted from studying either infection in isolation, and this was associated with a blunted local (pulmonary and peritoneal) and systemic inflammatory response and decreased ability to clear infection.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Enjae
authors.initials: E
authors.lastname: Jung
authors.forename: Erin E
authors.initials: EE
authors.lastname: Perrone
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liang
authors.forename: Elise R
authors.initials: ER
authors.lastname: Breed
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Dominguez
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Clark
authors.forename: Amy C
authors.initials: AC
authors.lastname: Fox
authors.forename: W Michael
authors.initials: WM
authors.lastname: Dunne
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Burd
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018893:Bronchoalveolar Lavage; D016207:Cytokines / Q000737:chemistry* / Q000276:immunology; D004195:Disease Models, Animal; D007958:Leukocyte Count; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D011023:Pneumonia, Staphylococcal / Q000097:blood* / Q000276:immunology / Q000473:pathology; D018805:Sepsis / Q000097:blood* / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines