TNF-alpha Decreases Pseudomonas aeruginosa-induced Mortality in Burned Mice through Negative Regulation of IL-1beta (35.2)

Abstract

Abstract Pseudomonas has emerged as an important source of burn wound sepsis. Anti-Tumor necrosis factor (TNF-α) therapy has been failed in decreasing mortality of sepsis patients. To evaluate the role of TNF-α and toll-like receptors in P. aeruginosa infection-induced mortality in thermal injured mice, we injected 109 P. aeruginosa in the back of the wild type (WT) mice, Tnfrsf1a-/- mice, and TLR4-/- mice at 8 hr after 30% total body surface area (TBSA) burn. At 24 hr after burn, animals were killed. Burn with P. aeruginosa injection did not induce lung damage in TLR4-/- mice but increased the mortality; blood and lung bacterial counts; pulmonary microvascular dysfunction; and IL-1β expression in Tnfrsf1a-/- mice compared with WT mice. However, burn with P. aeruginosa injection induced an increase of NF-κB activity of lung in WT mice but not in Tnfrsf1a-/- mice. Injection of Anakinra, a specific IL-1β inhibitor, decreased IL-1β expression, blood and lung bacterial counts; and pulmonary microvascular dysfunction in Tnfrsf1a-/- mice. Collectively, the block of the TNF-α receptor induces an increase of P. aeruginosa-induced IL-1β expression, lung permeability, and mortality in thermal injury through the inhibition of NF-κB. IL-1β inhibition reverses its effect and decreases the pulmonary permeability. Using IL-1β inhibitor to decrease anti-TNF-α therapy-induced lung permeability could be a promising therapeutic strategy in decreasing mortality in sepsis patients.