sPLA2-IIA inhibitor Tricyclic Dipyrido Diazepinone derivative 6 f suppresses poultry organic dust-induced pulmonary inflammation by downregulating ERK1/2-cPLA2 pathway.
| Title: | sPLA2-IIA inhibitor Tricyclic Dipyrido Diazepinone derivative 6 f suppresses poultry organic dust-induced pulmonary inflammation by downregulating ERK1/2-cPLA2 pathway. |
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| Authors: | Urs D; Inflammation Research Laboratory, Department of Studies & Research in Biochemistry, Mangalore University, Jnana Kaveri Post Graduate Centre, Kodagu, 571232, India.; Rahman A; Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur, Chikkamagaluru 577548, India.; Shuba HS; Inflammation Research Laboratory, Department of Studies & Research in Biochemistry, Mangalore University, Jnana Kaveri Post Graduate Centre, Kodagu, 571232, India.; Satyanarayan ND; Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre, Kadur, Chikkamagaluru 577548, India.; Meti RS; Inflammation Research Laboratory, Department of Studies & Research in Biochemistry, Mangalore University, Jnana Kaveri Post Graduate Centre, Kodagu, 571232, India.; Dharmappa KK; Inflammation Research Laboratory, Department of Studies & Research in Biochemistry, Mangalore University, Jnana Kaveri Post Graduate Centre, Kodagu, 571232, India. Electronic address: dharmappa@gmail.com. |
| Source: | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2026 Jan; Vol. 194, pp. 118869. Date of Electronic Publication: 2025 Dec 13. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 8213295 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1950-6007 (Electronic) Linking ISSN: 07533322 NLM ISO Abbreviation: Biomed Pharmacother Subsets: MEDLINE |
| Imprint Name(s): | Publication: Paris : Editions Scientifiques Elsevier; Original Publication: New York, N.Y. : Masson Pub. USA, Inc., c1982- |
| MeSH Terms: | Pneumonia*/drug therapy ; Pneumonia*/enzymology ; Pneumonia*/pathology ; Pneumonia*/prevention & control ; MAP Kinase Signaling System*/drug effects ; Group II Phospholipases A2*/antagonists & inhibitors ; Group II Phospholipases A2*/metabolism ; Dust*; Down-Regulation/drug effects ; Cytokines/metabolism ; Lung/drug effects ; Lung/pathology ; Lung/enzymology ; Animals ; Mice, Inbred BALB C ; Humans ; A549 Cells ; Mice ; Male |
| Abstract: | Poultry farm workers are highly susceptible to developing lung inflammatory diseases (asthma, COPD, ARDS, and ALI) due to prolonged exposure to organic dust and other airborne irritants in confined poultry facilities. Secretory phospholipase A2 (sPLA2-IIA) is a vital proinflammatory enzyme play an important role in the production of inflammatory mediators. Hence, this study examined the regulatory role of secretory phospholipase A2 enzyme in poultry dust induced lung inflammation in in vitro and in vivo models. Lung epithelial A549 cells and BALB/c mice treated with poultry dust increased the sPLA2-IIA mRNA expression and stimulated the induction of inflammatory symptoms. Inhibition of sPLA2 enzyme activity by Tricyclic Dipyrido Diazepinone derivative 6 f (sPLA2 inhibitor) markedly ameliorated ODE-induced lung histopathological conditions, decreased lung edema, cellular infiltration, and protein secretion. Further, downregulated activation of cPLA2 via decreasing phosphorylation of ERK1/2 and p38. Suppressing cPLA2 signalling cascade significantly reduced the production of inflammatory cytokines (IL-6, IL-8, and TNF-α) and chemokines (MIP-1, MCP, and RANTES). Consequently, the activation of COX-2 and the production of prostaglandin E2 and thromboxane B2 were significantly decreased. Conclusively, these findings indicated that sPLA2-IIA could potentially serve as a novel therapeutic target for treating lung inflammation in disease conditions.; (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.) |
| Competing Interests: | Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that no other persons have satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing, we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including the Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address, which is accessible by the Corresponding Author. |
| Contributed Indexing: | Keywords: Lung inflammation; Tricyclic Dipyrido Diazepinone; cPLA(2); organic dust extract; prostaglandins; sPLA(2)-IIA |
| Substance Nomenclature: | 0 (Dust); EC 3.1.1.4 (Group II Phospholipases A2); 0 (Cytokines) |
| Entry Date(s): | Date Created: 20251214 Date Completed: 20260110 Latest Revision: 20260110 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.biopha.2025.118869 |
| PMID: | 41391347 |
| Database: | MEDLINE |
Journal Article