Mechanisms of methicillin-resistant staphylococcus aureus pneumonia-induced intestinal epithelial apoptosis

Erin E. Perrone, Enjae Jung, Elise Breed, Jessica A. Dominguez, Zhe Liang, Andrew T. Clark, W. Michael Dunne, Eileen M. Burd, Craig M. Coopersmith

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia-induced sepsis is a common cause of morbidity in the intensive care unit. Although pneumonia is initiated in the lungs, extrapulmonary manifestations occur commonly. In light of the key role the intestine plays in the pathophysiology of sepsis, we sought to determine whether MRSA pneumonia induces intestinal injury. FVB/N mice were subjected to MRSA or sham pneumonia and killed 24 h later. Septic animals had a marked increase in intestinal epithelial apoptosis by both hematoxylin-eosin and active caspase 3 staining. Methicillin-resistant S. aureus-induced intestinal apoptosis was associated with an increase in the expression of the proapoptotic proteins Bid and Bax and the antiapoptotic protein Bcl-x L in the mitochondrial pathway. In the receptor-mediated pathway, MRSA pneumonia induced an increase in Fas ligand but decreased protein levels of Fas, FADD, pFADD, TNF-R1, and TRADD. To assess the functional significance of these changes, MRSA pneumonia was induced in mice with genetic manipulations in proteins in either the mitochondrial or receptor-mediated pathways. Both Bid -/- mice and animals with intestine-specific overexpression of Bcl-2 had decreased intestinal apoptosis compared with wild-type animals. In contrast, Fas ligand -/- mice had no alterations in apoptosis. To determine if these findings were organism-specific, similar experiments were performed in mice subjected to Pseudomonas aeruginosa pneumonia. Pseudomonas aeruginosa induced gut apoptosis, but unlike MRSA, this was associated with increased Bcl-2 and TNF-R1 and decreased Fas. Methicillin-resistant S. aureus pneumonia thus induces organism-specific changes in intestinal apoptosis via changes in both the mitochondrial and receptor-mediated pathways, although the former may be more functionally significant.

Original languageEnglish (US)
Pages (from-to)68-75
Number of pages8
JournalShock
Volume38
Issue number1
DOIs
StatePublished - Jul 1 2012

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Keywords

  • Bax
  • Bcl-2
  • Bid
  • Fas Ligand
  • Pseudomonas aeruginosa
  • Sepsis
  • cell death
  • gut

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Perrone, E. E., Jung, E., Breed, E., Dominguez, J. A., Liang, Z., Clark, A. T., Dunne, W. M., Burd, E. M., & Coopersmith, C. M. (2012). Mechanisms of methicillin-resistant staphylococcus aureus pneumonia-induced intestinal epithelial apoptosis. Shock, 38(1), 68-75. https://doi.org/10.1097/SHK.0b013e318259abdb