CysLT x LTB4

Condition of asthma in patients with asthma and concomitant seasonal allergic rhinitis (SAR) deteriorates during the Japanese cedar pollen (JCP) season. However, the underlying mechanisms remain unclear.

We analyzed seasonal variations in eicosanoid levels in the airways of patients with asthma and concomitant SAR sensitized to JCP (N = 29, BA-SAR-JCP group) and those not sensitized (N = 13, BA-AR-non-JCP group) during the JCP season. The association between changes in eicosanoid concentrations and pulmonary function was assessed. Exhaled breath condensate (EBC) was collected, and pulmonary function tests were performed during the JCP and non-JCP seasons. The cysteinyl leukotriene (CysLT), thromboxane B₂ (TXB₂), prostaglandin D₂-methoxime (PGD₂-MOX), and leukotriene B₄ (LTB₄) levels in the collected EBC were measured via enzyme-linked immunosorbent immunoassays.

The log CysLT levels significantly increased in the BA-SAR-JCP group during the JCP season compared with the non-JCP season (1.78 ± 0.55, 1.39 ± 0.63 pg/mL, mean ± standard deviation, respectively, p = 0.01) and those in the BA-AR-non-JCP group during the JCP season (1.39 ± 0.38 pg/mL, p = 0.04). Moreover, the log TXB₂ levels seemed to increase. However, the log LTB₄ and log PGD₂-MOX levels did not increase. The changes in the log CysLT levels during the two seasons were negatively correlated to forced expiratory volume in one second (FEV₁) in the BA-SAR-JCP group (r = -0.52, p < 0.01).

In the BA-SAR-JCP group, seasonal increases in eicosanoid levels in the airway likely promoted deterioration in pulmonary function despite optimal maintenance treatment.

Aspirin-exacerbated respiratory disease (AERD) is characterized by severe, sometimes life-threatening reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Mechanisms driving the disease include overproduction of leukotrienes and loss of anti-inflammatory prostaglandin E₂ (PGE₂) production. Many cell types contribute to the disease; however, eosinophils are markedly elevated and are important drivers of pathologic findings.

To investigate the capacity of aspirin and NSAIDs to drive eosinophil activation and the ability of PGE₂ to inhibit this activation.

Eosinophils were purified from blood of healthy individuals without AERD and stimulated with lysine aspirin, ketorolac, or sodium salicylate. The role of PGE₂ in altering activation was determined by incubating eosinophils with increasing doses of PGE₂ before lysine aspirin stimulation. Specific PGE₂ receptor use was determined by incubating eosinophils with receptor agonists and antagonists before aspirin stimulation. Cysteinyl leukotrienes (CysLTs), leukotriene B₄ (LTB₄), and eosinophil-derived neurotoxin (EDN) were quantified by enzyme-linked immunosorbent assay.

Stimulation of eosinophils with lysine aspirin, ketorolac, or sodium salicylate resulted in secretion of CysLTs and LTB₄ in the absence of EDN release. Low doses of PGE₂ inhibited LTB₄ and CysLT release, an effect lost at higher PGE₂ concentrations. Use of butaprost, an EP₂ receptor agonist, suppressed lysine aspirin stimulation. This mechanism was supported by blocking activity of the EP₁ and EP₃ receptors.

Eosinophils can be directly activated by NSAIDs via cyclooxygenase-independent pathways to produce CysLTs and LTB₄. This effect can be inhibited by PGE₂ acting through the EP₂ receptor. The recognized loss of EP₂ receptor expression combined with low PGE₂ levels explains in part the sensitivity to NSAIDs.

Though cyclooxygenase inhibitors are employed in rheumatoid arthritis treatment, modulators of leukotrienes are underexplored. We investigated the therapeutic potential of montelukast, a known cysteinyl leukotriene receptor-1 (CysLT1) inhibitor in an experimental rat model of arthritis.

Arthritis was induced in rats, and montelukast (5 mg/kg body wt.) was administered prophylactically (PAM) and therapeutically (TAM) through oral route.

Blood and joint tissue markers of oxidative stress (lipid peroxidation, protein carbonyls, and nitric oxides) were significantly (p < 0.05) reduced in montelukast administered rats. Paw inflammation, RA markers (RF and CRP), eicosanoids (PGE₂, LTB₄, and LTC₄), cytokines (IL-1β and MCP-1), activity of hydrolytic enzymes (collagenase, elastase, and hyaluronidase), expression of matrix metalloproteinases (MMP), and EP-4 receptor were significantly (p < 0.05) reduced in montelukast administered rats. This study established that leukotriene inhibition through montelukast lowered the severity of arthritis and thus a potential strategy for reducing the severity of arthritis.