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.