Leukotrienes in pulmonary arterial hypertension

Abstract

Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism and are markers and mediators of pulmonary inflammation. Research over the past two decades has established that LTs modulate inflammation in pulmonary arterial hypertension (PAH). The purpose of this review was to summarize the current knowledge of LTs in the pathophysiology of PAH and to highlight a recent study that advances our understanding of how leukotriene B4 (LTB4) specifically contributes to pulmonary vascular remodeling. The results of these studies suggest that pharmacological inhibition of LT pathways, especially LTB4, has high potential for the treatment of PAH.

Fig. 1

LT pathways and functions in PAH. LTs are synthesized from the arachidonic acid (AA) pathway, where 5-LO works together with FLAP on the perinuclear membrane that converts AA to LTA₄. LTA₄ is quickly metabolized to LTB₄ by LTA₄H, or is converted to LTC₄ by LTC₄S. LTC₄ undergoes sequential peptide cleavage of the glutathione moiety to form LTD₄ or LTE₄. LTB₄ may function as a transcriptional regulator in the nucleus or is transported out from the source cell and binding to its cognate receptors (BLT1 and BLT2) to initiate the downstream signaling. In PAH, elevated LTB₄ signaling around the disease arteriole results in the recruitment of the leukocytes. Recent data demonstrate that LTB₄ may also cause vascular remodeling by inducing the PAEC apoptosis and PASMC proliferation