Abstract
BackgroundMice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8–10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis.MethodsAged (20–24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival.ResultsIn contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice.ConclusionsBlocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.
Highlights
Sepsis affects over 800,000 patients annually in the United States, and between 230,000 and 370,000 patients die of the disease annually [1]
We previously studied the impact of sepsis in young (8– 10 week old) mice with defective chylomicron assembly induced by conditional intestine-specific deletion of Microsomal triglyceride transfer protein (Mttp) (Mttp-IKO mice) [59]
To determine the functional significance of impaired lipid transport, aged wild type (WT) and Mttp-IKO mice were subjected to P. aeruginosa pneumonia and followed 7 days for survival (Figure 1)
Summary
Sepsis affects over 800,000 patients annually in the United States, and between 230,000 and 370,000 patients die of the disease annually [1]. Even though elderly patients account for slightly greater than 10% of the population in the United States, more than 60% of cases of sepsis and approximately 80% of deaths occur in patients over 65 years of age [2,3]. Both animal and human studies demonstrate that age greatly impacts the host response following sepsis and is mortality higher with aging, and multiple therapies that are effective in young mice are ineffective in aged mice [4,5,6,7,8,9,10,11,12]. The purpose of this study was to determine whether age impacts outcome in MttpIKO mice subjected to sepsis
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