Murine Lung Cancer Increases CD4+ T Cell Apoptosis and Decreases Gut Proliferative Capacity in Sepsis.

• Type of Material: Article
• Authors: John D. Lyons, Emory University; Rohit Mittal, Emory University; Katherine T. Fay, Emory University; Ching-Wen Chen, Emory University; Zhe Liang, Emory University; Lindsay M. Margoles, Emory University; Eileen Burd, Emory University; Alton Farris III, Emory University; Mandy Ford, Emory University; Craig Coopersmith, Emory University
• Language: English
• Date: 2016-03-28
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Lyons et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0149069
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 11
• Issue: 3
• Start Page: e0149069
• End Page: e0149069
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health (GM104323, GM095442, GM072808, GM109779, GM113228).
• Keywords: Cytokines; Mouse models; Lymphocytes; T cells; Sepsis; Apoptosis; Gastrointestinal tract; Lung and intrathoracic tumors
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

BACKGROUND: Mortality is significantly higher in septic patients with cancer than in septic patients without a history of cancer. We have previously described a model of pancreatic cancer followed by sepsis from Pseudomonas aeruginosa pneumonia in which cancer septic mice have higher mortality than previously healthy septic mice, associated with increased gut epithelial apoptosis and decreased T cell apoptosis. The purpose of this study was to determine whether this represents a common host response by creating a new model in which both the type of cancer and the model of sepsis are altered. METHODS: C57Bl/6 mice received an injection of 250,000 cells of the lung cancer line LLC-1 into their right thigh and were followed three weeks for development of palpable tumors. Mice with cancer and mice without cancer were then subjected to cecal ligation and puncture and sacrificed 24 hours after the onset of sepsis or followed 7 days for survival. RESULTS: Cancer septic mice had a higher mortality than previously healthy septic mice (60% vs. 18%, p = 0.003). Cancer septic mice had decreased number and frequency of splenic CD4+ lymphocytes secondary to increased apoptosis without changes in splenic CD8+ numbers. Intestinal proliferation was also decreased in cancer septic mice. Cancer septic mice had a higher bacterial burden in the peritoneal cavity, but this was not associated with alterations in local cytokine, neutrophil or dendritic cell responses. Cancer septic mice had biochemical evidence of worsened renal function, but there was no histologic evidence of renal injury. CONCLUSIONS: Animals with cancer have a significantly higher mortality than previously healthy animals following sepsis. The potential mechanisms associated with this elevated mortality differ significantly based upon the model of cancer and sepsis utilized. While lymphocyte apoptosis and intestinal integrity are both altered by the combination of cancer and sepsis, the patterns of these alterations vary greatly depending on the models used.