Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase-Activating protein in lung tissue.

BACKGROUND: Post-traumatic lung injury following trauma and hemorrhagic shock (T/HS) is associated with significant morbidity. Leukotriene-induced inflammation has been implicated in the development of post-traumatic lung injury through a mechanism that is only partially understood. Postshock mesenteric lymph returning to the systemic circulation is rich in arachidonic acid, the substrate of 5-lipoxygenase (ALOX5). ALOX5 is the rate-limiting enzyme in leukotriene synthesis and, following T/HS, contributes to the development of lung dysfunction. ALOX5 colocalizes with its cofactor, 5-lipoxygenase-activating protein (ALOX5AP), which is thought to potentiate ALOX5 synthetic activity. We hypothesized that T/HS results in the molecular association and nuclear colocalization of ALOX5 and ALOX5AP, which ultimately increases leukotriene production and potentiates lung injury. MATERIALS AND METHODS: To examine these molecular interactions, a rat T/HS model was used. Post-T/HS tissue was evaluated for lung injury through both histologic analysis of lung sections and biochemical analysis of bronchoalveolar lavage fluid. Lung tissue was immunostained for ALOX5 and ALOX5AP with association and colocalization evaluated by fluorescence resonance energy transfer. In addition, rats undergoing T/HS were treated with MK-886, a known ALOX5AP inhibitor. RESULTS: ALOX5 levels increase and ALOX5/ALOX5AP association occurred after T/HS, as evidenced by increases in total tissue fluorescence and fluorescence resonance energy transfer signal intensity, respectively. These findings coincided with increased leukotriene production and with the histological changes characteristic of lung injury. ALOX5/ALOX5AP complex formation, leukotriene production, and lung injury were decreased after inhibition of ALOX5AP with MK-886. CONCLUSIONS: These results suggest that the association of ALOX5/ALOX5AP contributes to leukotriene-induced inflammation and predisposes the T/HS animal to lung injury.

Association of the -1072G/A polymorphism in the LTC4S gene with asthma in an Indian population.

BACKGROUND: Atopic asthma, the most common chronic disease affecting children and young adults, is a complex disorder with variable phenotypes. Cysteine leukotrienes (Cys-LTs) are powerful bronchoconstrictors and play a critical role in airway inflammation and remodeling that are characteristic of asthma. OBJECTIVE: To investigate the association of ALOX5, LTC4S and CysLTR2 gene polymorphisms with atopic asthma in an Indian population. METHODS: A total of 19 single nucleotide polymorphisms (SNPs) within these genes were genotyped in a family-based cohort (n = 239) and a case-control cohort (139 cases and 194 controls) followed by association analyses. RESULTS: We found a significant association of the -1072G/A (rs3776944) SNP with atopic asthma in the family-based association analysis (p = 0.0004). These results were also replicated in the case-control cohort (p = 0.009). The allele A was negatively associated with atopic asthma. We also noted a significant association in the two-locus (rs3776944G/A and rs730012A/C) haplotypic analysis of this gene both in the family-based (p = 0.03) and the case-control (p = 0.02) analyses. CONCLUSION: This study supports the role of the LTC4S gene polymorphism in genetic susceptibility to atopic asthma in an Indian population.