O23 – Association of Inflammasomes and Caspase-1 Mediated Cardiac Dysfunction with Sepsis

Author(s):

Deborah Carlson, Steven Wolf, University of Texas Southwestern Medical Center

Background: Each year in the US, there are approximately 2.5 million incidences of sepsis requiring attention, accounting for >100,000 hospitalizations and 12,000 deaths. Experimental and clinical studies have documented that patients with sepsis, experience cardiac dysfunction, and that non-survivors have significantly lower ventricular ejection fractions, and higher right ventricular end diastolic volumes than do survivors. We have shown that a family of cysteine proteases termed caspases, are directly associated with murine cardiac dysfunction following septic trauma. Caspase-1(Cas1) is known to induce apoptosis, and also cleave the precursor forms of IL-1 and IL-18 into active peptides, suggesting that Cas1 is a key player in the inflammatory response.

Hypothesis: To investigate the involvement of Cas1 in cardiac dysfunction after septic injury. The role of Cas1 in the inflammatory response both systemically and in the myocardium
following septic injury was also investigated.

Methods: NOD.129S2(B6)-Casp1tm1Sesh/LtJ (Cas1-/-) and NOD/ShiLtJ (Cas1+/+) mice were injected IP with 4mg/kg of E. coli 0111:B4 lipopolysaccharide (LPS) in a total of 0.5 ml, or PBS. Serum and hearts were collected at 4,8,12,18 and 24 hr post injection for analysis of serum IL-1, TNF, IL-6, MIF, and IL-10. qPCR analysis of myocardial IL-1, TNF, IL-6, MIF, and IL-10 expression. Fractional shortening was measured using M-mode echocardiography. TUNEL staining was performed from harvested hearts

Results: Loss of the Cas1 gene resulted in global changes in both circulating and cardiac specific cytokine expression at all time points examined post septic injury. A significant reduction in both TNF, as well as IL-1 was noted. mRNA expression in the heart significantly differed with the absence of Cas1. Specifically, there was no detectable increase over control at any time point besides 24hrs for IL-6, IL-10, and IL-1 beta. There was a significant increase in fractional shortening in Cas1-/- mice relative to Cas1+/+ mice at 2 hours (Cas1+/+ 52.7% vs. Cas1-/- 65.9%, p=0.042) and 24 hours (Cas1+/+ 46.8% vs. Cas1-/- 63.6%, p=0.032).

Conclusions: Lack of Cas1 resulted in a decreased expression of known inflammatory cytokines during sepsis, and ameliorated myocardial dysfunction in septic mice. The increased cardiac function seen with the lack of upregulation of IL-1beta in the myocardium suggests an important role for the inflammasome and its activation in sepsis