The Acute Inflammatory Response in Trauma / Hemorrhage and Traumatic Brain Injury: Current State and Emerging Prospects

Traumatic injury/hemorrhagic shock (T/HS) elicits an acute inflammatory response that may result in death. Inflammation describes a coordinated series of molecular, cellular, tissue, organ, and systemic responses that drive the pathology of various diseases including T/HS and traumatic brain injury (TBI). Inflammation is a finely tuned, dynamic, highly-regulated process that is not inherently detrimental, but rather required for immune surveillance, optimal post-injury tissue repair, and regeneration. The inflammatory response is driven by cytokines and chemokines and is partially propagated by damaged tissue-derived products (Damage-associated Molecular Patterns; DAMP's). DAMPs perpetuate inflammation through the release of pro-inflammatory cytokines, but may also inhibit anti-inflammatory cytokines. Various animal models of T/HS in mice, rats, pigs, dogs, and non-human primates have been utilized in an attempt to move from bench to bedside. Novel approaches, including those from the field of systems biology, may yield therapeutic breakthroughs in T/HS and TBI in the near future

Nitric oxide production after acute, unilateral hydrochloric acid- induced lung injury in a canine model

Objective: To determine if acute unilateral lung injury induces only local or systemic inflammatory effects by measuring the production of nitric oxide (No) and its metabolites (nitrites and nitrates) in the injured and the contralateral lung and the blood initially and 4 hrs after injury. Design: Unilateral hydrochloric acid instillation in split lung intubated subject studied over time. Setting: Animal physiology laboratory. Subjects: Five mongrel dogs. Interventions: Instillation of 10 mL of 0.1 N hydrochloric acid into one lung via a plastic catheter. Bronchoalveolar lavage (BAL) was done at 4 hrs. Measurements and Main Results: Unilateral acid instillation did not alter systemic blood pressure or cardiac output, nor did it induce arterial hypoxemia. The BAL nitrite and nitrate level on the side of injury was higher than the control side (3.6 ±1.36 vs. 1.5 ± 1.58 mM, p < .05), and serum nitrites and nitrates levels also decreased from the levels before acid instillation levels (p < .05). Exhaled NO levels were measured only in three animals. The levels increased acutely on hydrochloric acid instillation from only the injured lung and returned to baseline over several minutes. However, the level of exhaled NO from the injured lung failed to increase 4 hrs after injury, despite the increase in BAL nitrites and nitrates. Conclusions: Acute unilateral lung injury in the dog results in increased NO production that is compartmentalized to the injured lung. The increase in exhaled NO after injury is transient and does not allow one to monitor the progress of lung injury

Fatty acid binding protein-4 (FABP4) is a hypoxia inducible gene that sensitizes mice to liver ischemia/re-perfusion injury

BACKGROUND & AIMS: Fatty acid binding protein 4 (FABP4) has been known as a mediator of inflammatory response in the macrophages and adipose tissue, but its hepatic function is poorly understood. The goal of this study is to investigate the role of FABP4 in liver ischemia/reperfusion (I/R), a clinical condition involves both hypoxia and inflammation. METHODS: To examine the I/R regulation of FABP4, mice were subjected to I/R surgery before being measured for FABP4 gene expression. Both loss-of-function (by using a pharmacological FABP4 inhibitor) and gain-of-function (by adenoviral overexpression of FABP4) were used to determine the functional relevance of FABP4 expression and its regulation during I/R. To determine the hypoxia responsive regulation of FABP4, primary mouse hepatocytes were exposed to hypoxia. The FABP4 gene promoter was cloned and its regulation by hypoxia inducible factor 1α (HIF-1α) was characterized by luciferase reporter gene, electrophoretic mobility shift, and chromatin immunoprecipitation assays. RESULTS: We found that the hepatic expression of FABP4 was markedly induced by I/R. At the functional level, pharmacological inhibition of FABP4 alleviated the I/R injury, whereas adenoviral overexpression of FABP4 sensitized mice to I/R injury. We also showed that exposure of primary hepatocytes to hypoxia or transgenic overexpression of HIF-1α in the mouse liver was sufficient to induce the expression of FABP4. Our promoter analysis established FABP4 as a novel transcriptional target of HIF-1α. CONCLUSIONS: FABP4 is a hypoxia inducible gene that sensitizes mice to liver I/R injury. FABP4 may represent a novel therapeutic target, and FABP4 inhibitors may be used as therapeutic agents to manage hepatic I/R injury

Definition and pathogenesis of septic shock

SCOPUS: ar.kinfo:eu-repo/semantics/publishe