Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality

Amy C. Fox, Elise R. Breed, Zhe Liang, Andrew T. Clark, Brendan R. Zee-Cheng, Katherine C. Chang, Jessica A. Dominguez, Enjae Jung, W. Michael Dunne, Eileen M. Burd, Alton B. Farris, David C. Linehan, Craig M. Coopersmith

Research output: Contribution to journalArticle

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Abstract

Lymphocyte apoptosis is thought to have a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, because the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with preexisting cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later, after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced Tand B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared with WT mice following P. aeruginosa pneumonia (85 versus 44% 7-d mortality; p = 0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify that the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim-/- mice. Septic Bim-/- mice with cancer also had increased mortality compared with septic WT mice with cancer. These data demonstrate that, despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia.

Original languageEnglish (US)
Pages (from-to)1950-1956
Number of pages7
JournalJournal of Immunology
Volume187
Issue number4
DOIs
StatePublished - Aug 15 2011
Externally publishedYes

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Lymphocytes
Apoptosis
Mortality
Neoplasms
Sepsis
Pseudomonas aeruginosa
Comorbidity
Pneumonia
Cytokines
Survival
Bronchoalveolar Lavage Fluid
Interleukin-10
Healthy Volunteers
Adenocarcinoma
B-Lymphocytes
Animal Models
Pathology
Cell Line
Lung
Injections

ASJC Scopus subject areas

  • Immunology

Cite this

Fox, A. C., Breed, E. R., Liang, Z., Clark, A. T., Zee-Cheng, B. R., Chang, K. C., ... Coopersmith, C. M. (2011). Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality. Journal of Immunology, 187(4), 1950-1956. https://doi.org/10.4049/jimmunol.1003391

Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality. / Fox, Amy C.; Breed, Elise R.; Liang, Zhe; Clark, Andrew T.; Zee-Cheng, Brendan R.; Chang, Katherine C.; Dominguez, Jessica A.; Jung, Enjae; Dunne, W. Michael; Burd, Eileen M.; Farris, Alton B.; Linehan, David C.; Coopersmith, Craig M.

In: Journal of Immunology, Vol. 187, No. 4, 15.08.2011, p. 1950-1956.

Research output: Contribution to journalArticle

Fox, AC, Breed, ER, Liang, Z, Clark, AT, Zee-Cheng, BR, Chang, KC, Dominguez, JA, Jung, E, Dunne, WM, Burd, EM, Farris, AB, Linehan, DC & Coopersmith, CM 2011, 'Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality', Journal of Immunology, vol. 187, no. 4, pp. 1950-1956. https://doi.org/10.4049/jimmunol.1003391
Fox AC, Breed ER, Liang Z, Clark AT, Zee-Cheng BR, Chang KC et al. Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality. Journal of Immunology. 2011 Aug 15;187(4):1950-1956. https://doi.org/10.4049/jimmunol.1003391
Fox, Amy C. ; Breed, Elise R. ; Liang, Zhe ; Clark, Andrew T. ; Zee-Cheng, Brendan R. ; Chang, Katherine C. ; Dominguez, Jessica A. ; Jung, Enjae ; Dunne, W. Michael ; Burd, Eileen M. ; Farris, Alton B. ; Linehan, David C. ; Coopersmith, Craig M. / Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality. In: Journal of Immunology. 2011 ; Vol. 187, No. 4. pp. 1950-1956.
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abstract = "Lymphocyte apoptosis is thought to have a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, because the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with preexisting cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later, after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced Tand B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared with WT mice following P. aeruginosa pneumonia (85 versus 44{\%} 7-d mortality; p = 0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify that the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim-/- mice. Septic Bim-/- mice with cancer also had increased mortality compared with septic WT mice with cancer. These data demonstrate that, despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia.",
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