Effects of tyrosine kinase signaling inhibition on survival after cecal ligation and puncture in diet-restricted mice

Background: Malnutrition impairs host immunity, resulting in high mortality and morbidity due to infections. Phosphorylation of protein tyrosine kinas e (PTK) is a key step in the signaling of many cellular functions, includin g immune cell functions. Malnutrition may affect this signaling in response to surgical insults. The aim of this study was to examine the effects of P TK inhibition on mortality in ad libitum and in diet-restricted mice after cecal ligation and puncture (CLP). Moreover, tyrosine phosphorylation of pe ritoneal cells from these animals was evaluated. Methods: Survival study: M ice (n = 45) received chow, 146 g/kg per day (ad libitum) or 36.5 g/kg per day (diet-restricted), for 7 days. Two hours before CLP, one-half the mice in each group were given a tyrosine kinase inhibitor, AG 556 (3.0 mg/kg i.p .), and the others received vehicle. Survival was observed up to 7 days aft er CLP. Effects of AG 556 on survival with a lesser degree of malnutrition (chow 73 g/kg per day) were also examined (n = 41). Measurement of tyrosine phosphorylation: mice (n = 20) were assigned to the ad libitum and diet-re stricted (chow 36.5 g/kg per day) groups. Peritoneal cells were harvested e ither before or 2 hours after glycogen injection. Glycogen treatment elicit s polymorphonuclear neutrophil influx into the peritoneal cavity. The cells were incubated with or without N-formyl-methionyl-leucyl-phenylalanine (fM LP). Tyrosine phosphorylation in the cells was examined using flow cytometr y, laser scanning cytometry, and Western blotting. Results: Diet restrictio n significantly reduced survival compared with the ad libitum group. AG 556 treatment decreased the survival of ad libitum, but not in diet-restricted mice in both survival experiments. Stimulation of peritoneal cells with fM LP increased tyrosine phosphorylation in the ad libitum group (23% increase before glycogen and 18% after glycogen), but not in the diet-restricted gr oup (-9% before glycogen and 3% after glycogen). Conclusions: Inhibition of tyrosine kinase signaling impairs the ability of a well-nourished host to survive CLP-induced sepsis, while having no effects on survival in diet-res tricted mice. Peritoneal cells from diet-restricted animals are unable to i ncrease PTK phosphorylation in response to stimulation, which may be the me chanism underlying impaired host defense during malnutrition.