Production of reactive oxygen species ROS during

Production of reactive oxygen species (ROS) during RSV infection is one the important ways that neutrophils can injure the lungs [2], [24], [25]. Lipoxygenases are considered as an important source of producing ROS inside the EIPA receptor [26]. Several studies have indicated that the 12/15-LOX is a pro-inflammatory pathway and mediates an elevation in inflammation and oxidative stress in different tissues [27]. Therefore LOX inhibitors have a protective effect in inflammatory diseases because of their anti-inflammatory activity [26]. Based on pervious strong supportive evidences indicating that RSV-induced intracellular ROS formation [23] and our results revealing the expression of pro-inflammatory mediators and 12/15 LOX, it can be accounts as an important pathogenetic mechanism of RSV-induced lung disease, and anti-LOX products intervention may represent a rational approach for treatment of RSV [15]. Adhesion molecules also are involved in the pathophysiology of RSV-associated diseases [28]. In RSV infection, ICAM-1, VCAM-1, and E-selectin are involved in neutrophil interactions with the endothelium [28], [29]. Neutrophils are the predominant airway leukocytes invading the airways in RSV bronchiolitis [2], [29]. It was shown that 15(S)-HETE up-regulated the expression of E-selectin in the endothelial cells [30]. A threefold increase in the level of E-selectin in cultures treated with 15(S)-HETE compared to control was reported. One possible mechanism is the involvement of LOX pathway in the adhesion molecules expression such as ICAM-1, VCAM-1, and E-selectin and make an important role in leukocytes infiltration and RSV bronchiolitis.
Disclosure
Acknowledgments We thank the following people for their contributions to this work: Maryam Golara, Fatemeh Adjaminejad and Azadeh Shadab for the technical support. This research was supported by School of Public Health, Tehran University of Medical Sciences [92-01-27-21977].
Introduction The 12- lipoxygenase (LO) pathway is a potentially promising target to reduce AT inflammation, islet dysfunction and insulin resistance [[1], [2]]. The relevance of the pathway in insulin resistance is illustrated by several proof-of-concept studies in rodents. 12/15LO knockout mice are protected from insulin resistance in diet-induced obesity and 12/15LO expression is required for initiation of insulin resistance in obesity [[3], [4], [5], [6]]. 12/15LO expression is highly upregulated in adipocytes of high fat fed mice and its deletion protects mice from developing increases in pro-inflammatory cytokines, maintains normal adiponectin levels and fully maintains glycemic control compared to wild type mice fed the same diet [7]. Recent data indicate that direct addition of 12/15LO lipid products to fully differentiated 3T3L1 adipocytes leads to upregulation of pro-inflammatory cytokines and significant reduction of adiponectin [8]. Our group has demonstrated activation of the 12/15 and 5-LO pathways in AT, SVF and adipocytes in obese Zucker rats [9]. Importantly, studies from our laboratory showed that 12LO is upregulated in cytokine-treated human islets and that direct addition of 12-HETE leads to β cell dysfunction and loss of viability [[10], [11]]. An important aspect of 12 and 15- lipoxygenase pathways is production of pro-resolving mediators of inflammation from ω3 fatty acids such as DHA and EPA [[12], [13]]. These anti-inflammatory metabolites were carefully characterized and while their roles in resolving acute inflammation is well established their roles in chronic inflammatory conditions such as obesity and diabetes is just beginning to emerge [[14], [15]]. Also, importantly, only the 12(S)- and 15(S)- isomers are known to exert biological activity, while the (R) isomers are non-enzymatically generated primarily ex-vivo and lack biological activity. Therefore, characterization of both the pro- and anti-inflammatory biologically active metabolites of lipoxygenase pathways is of prime importance.