Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

Abstract

Lysophosphatidic acid (LPA), an intercellular lipid mediator, is increased in the bronchoalveolar fluids of patients with asthma after allergen exposure. LPA administration exaggerates allergic responses, and the type 2 LPA receptor (LPA2) has been reported as a therapeutic target for asthma. However, results with LPA2 agonist and antagonist along with LPA2 gene deficient mice have been controversial and contradictory. We compared the effects of LPA2 antagonist (H2L5186303) and agonist (GRI977143) in a single experimental protocol of ovalbumin (OVA)-induced allergic asthma by treating drugs before antigen sensitization or challenge. H2L5186303 showed strong suppressive efficacy when administered before OVA sensitization and challenge, such as suppression of airway hyper responsiveness, inflammatory cytokine levels, mucin production, and eosinophil numbers. However, GRI977143 showed significant suppression when administered before an OVA challenge. Increases in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid, Th2 cytokine levels, inflammatory scores, and mucin production were differentially ameliorated by the two drugs. The results demonstrate the multiple roles of LPA2 in asthmatic responses. We suggest that the development of LPA2 antagonists would achieve better therapeutic efficacy against asthma than agonists.

Group III secreted phospholipase A2‐driven lysophospholipid pathway protects against allergic asthma

“…Another study has shown that an LPA 2 antagonist attenuates allergic inflammation when treated before antigen sensitization, whereas an LPA 2 agonist suppressed it when administered before antigen challenge, in a single experimental protocol of OVA-induced asthma model, suggesting the roles of LPA 2 in multiple steps of asthmatic responses. 65 Based on these findings, the protective sPLA 2 -III-LPA 2 axis in the lung may be operative in the phase of antigen challenge, but not sensitization. Alternatively, as sPLA 2 has an antimicrobial activity and contributes to shaping of the microbiota, 66,67 whose compositional and functional changes often lead to immune and metabolic alterations in proximal and distal tissues, 68 it is possible that differences in microbiome, if any, in the lung, or in other tissues such as the intestine and skin where sPLA 2 -III expression is high, 46 among different facilities might have distinct impacts on lung pathology.…”

“…Indeed, in our preliminary study, sPLA 2 ‐III deficiency offers distinct effects on HDM‐induced allergic airway inflammation, which will be reported elsewhere. Another study has shown that an LPA 2 antagonist attenuates allergic inflammation when treated before antigen sensitization, whereas an LPA 2 agonist suppressed it when administered before antigen challenge, in a single experimental protocol of OVA‐induced asthma model, suggesting the roles of LPA 2 in multiple steps of asthmatic responses 65 . Based on these findings, the protective sPLA 2 ‐III‐LPA 2 axis in the lung may be operative in the phase of antigen challenge, but not sensitization.…”

Association between plasma lysophosphatidic acid levels and bronchopulmonary dysplasia in extremely preterm infants: A prospective study

“…The detailed mechanisms remain elucidated. Besides, blocking or deficient murine in LPA1, LPA2, or LPA3 signaling has been related to an anti‐inflammatory effect in various diseases, including experimental BPD, asthma, pulmonary fibrosis, and acute infection 9,29–32 . Considering inflammation is a crucial driver in BPD, the augmented LPA level in plasma might trigger an inflammatory response, thereby increasing inflammatory cytokines and contributing to BPD.…”

“…Besides, blocking or deficient murine in LPA1, LPA2, or LPA3 signaling has been related to an anti-inflammatory effect in various diseases, including experimental BPD, asthma, pulmonary fibrosis, and acute infection. 9,[29][30][31][32] Considering inflammation is a crucial driver in BPD, the augmented LPA level in plasma might trigger an inflammatory response, thereby increasing inflammatory cytokines and contributing to BPD. Furthermore, other LPA receptors like LPA4 and LPA6 have been suggested to be involved in vascular development and hemostasis, including endothelial viability, angiogenesis, and barrier function, [33][34][35][36] which can be another link between LPA and BPD.…”

Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases

“…Asthma therapy has been found to target LPA 2 . When administered before an antigen challenge or prior to sensitization, the LPA 2 antagonist H2L5186303 efficiently inhibits symptoms and immunological responses in BALA/c mice [71]. LPA upregulates the release of proinflammatory cytokines (such as IL-8) and PGE2 and attenuates the effect of Th2-type cytokines (such as IL-13).…”