Recently, the gut has been invoked as the central organ promoting the environment conducive for multi-organ failure (MOF). Following effective resuscitation, critically injured patients typically enter a hypermetabolic state. A secondary insult during this vulnerable period appears to be responsible for precipitating clinical MOF. We have developed a sequential insult rodent model to investigate the possible mechanisms involved in postinjury MOF. Our preliminary data suggests that limited gut ischemia/reperfusion I/R, (45 min SMA occlusion), followed by low dose endotoxin (2.5 mg/Kg IP) will produce MOF. Moreover, our animal work to date indicates a) the neutrophil (PMN) is an integral effector, b) xanthine oxidase (XO) mechanisms promote PMN mediated injury, c) phospholipase A2 (PLA2) is a proximal step in this exaggerated inflammatory process, and d) PLA2 blockade, even initiated after gut ischemia, attenuates organ failure thereby suggesting clinical relevance. Based on these findings, our working hypothesis is: postinjury gut I/R promotes remote organ injury by serving as a priming bed for circulating PMN's that are related to PLA2 activation.
Our specific aims are: 1. Does limited gut I/R (45 min SMA occlusion) produce lung injury (125I albumin leak, histology) and liver injury (125I albumin leak bile production, systemic ketone body ratio (KBR), histology)? 2. Does low dose endotoxin (2.5 mg/Kg) produce lung and liver injury? 3. Does limited gut I/R followed by low dose endotoxin synergistically produce lung and liver injury? 4. Do neutrophils (PMN's) have a mechanistic role in this sequential insult model myeloperoxidase (MPO), histology, PMN CD18/CD11b receptor blockade (R17 antibody)? 5. Does gut I/R prime circulating PMN's for superoxide production (FMLP)? 6. Is phospholipase A2 (PLA2) activation involved mechanistically with gut I/R induced PMN priming (PLA2 inhibition (quinacrine), platelet activating factor (PAF) blockade (WEB 2170)? 7. Does PLA2 inhibition abrogate lung and liver injury in this synergistic model? 8. Is there a therapeutic window (postischemia) that offers clinical relevance for PLA2 inhibition in the injured patient? Our ultimate goal is to decouple obligatory postinjury gut I/R from initiating MOF.
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