Introduction (2897 words)
Asthma is a chronic inflammatory disorder of the airways and is characterized by airway hyperresponsiveness and reversible airflow obstruction that fluctuates over time. It is also increasingly recognized as a disease with multiple phenotypes that differ in clinical severity, response to therapy, and long-term outcome1. Eicosanoids are a family of bioactive lipid mediators that regulate a wide variety of inflammatory processes2. Eicosanoid species are generated from ω-6- and ω-3-derived polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and eicosapentaenoic acid (EPA), respectively. AA can be converted into prostaglandins (PGs), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs)3 by cyclooxygenases (COXs), lipoxygenases (LOXs) and cytochrome P450 epoxygenases (CYP450). 5-LOX-derived LTA4 can be converted to lipoxins in the presence of 15-LOX, while 15-LOX generates 15-HETE3. Lipoxins and 15-HETE have been reported to exert anti-inflammatory activity via reducing activation and recruitment of inflammatory cells and modulating the expression of adhesion molecules; for example, LXA4and 15-HETE inhibit LTB4-induced chemotaxis of neutrophils in vitro and in vivo4-6. Thromboxane B2 (TXB2) is non-enzymatically hydrolyzed from COX-derived TXA2, a potent bronchial smooth muscle spasmogen formed by platelets7, is known to reduce T cell secretion of the Th1 cytokine, interferon-γ in vitro, which may favor T cell differentiation toward a Th2 cytokine profile8.
Together, these functionally diverse classes of eicosanoids are thought to play a critical role in maintaining homeostasis and have been an active area of investigation in assessing the mechanism underlying the pathogenesis of asthma and their potential utility as the inflammatory indicators in disease progression and treatment outcome. Indeed, several studies have suggested their roles as the biomarkers for screening, diagnosis, and, to a limited extent, monitoring the treatment outcome. For example, several independent studies have shown elevated levels of eicosanoids in the EBC of patients with asthma9,10, but due, perhaps in part, to the limited sample sizes and the heterogeneity of the study patient populations, unified evidence remains to be obtained. As the result, knowledge about eicosanoids in disease progression and therapeutic outcome remains incomplete, and their relationship with the disease status has yet to be comprehensively explored and their clinical utility as biomarkers remains to be defined. We have previously reported that in a pediatric study population in Taiwan, the levels of exhaled LTB4, LTE4, LXA4, and PGE2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB4 and LXA4, together with FeNO and FEV1, best characterized childhood asthma11. We described herein an analysis of the levels of exhaled eicosanoids differed at the time of acute exacerbation and convalescence and reported that the levels of TXB2 and 15-HETE were the most responsive to therapy.