Naftidrofuryl alleviates LPS-mediated inflammatory-oxidative and fibrotic successions in a rat model of acute lung injury: An emerging mechanistic role of PPARα/SIRT۱/ATF۳ axis

Objective(s): Platelet-released serotonin (۵-HT) is linked to lung inflammatory injury. Simultaneously, PPARα activation increases SIRT۱ activity, thereby regulating inflammatory damage in acute lung injury (ALI). Also, ATF۳ can prevent ALI-related inflammation and oxidative injury. However, the relationship between ۵-HT and PPARα/SIRT۱/ATF۳ in ALI remains ambiguous. Hence, exploring the impact of naftidrofuryl (NAFT), a ۵-HT۲A antagonist, on LPS-induced ALI in rats, particularly in combination with dexamethasone (DEXA), may be valuable, given the involvement of the PPARα/SIRT۱/ATF۳ axis. Our investigation identified targets and pathways associated with the therapeutic benefits of NAFT using network pharmacology and molecular docking. Materials and Methods: For in vivo validation, ۶۴ rats were allocated to ۸ groups. Lung W/D ratio and MPO activity were quantified. The BALF HO-۱, MDA, TAC, PPARα, SIRT۱, ATF۳, TNF-α, IL-۶, and IL-۱β levels were analyzed. Further, expressions of JAK۲, STAT۳, HMGB۱, AMPK, Nrf۲, and MyD۸۸ were assessed. Lung tissues were examined histologically and immunohistochemically to determine NF-κB, caspase-۳, and TGF-β۱ expression.Results: Network pharmacology disclosed ۱۷۶ intersecting targets between “NAFT-ALI” and “DEXA-ALI” with various KEGG pathways. Docking confirmed a strong affinity between NAFT and SIRT۱, HMGB۱, AMPK, and ATF۳. Experimentally, NAFT inhibited JAK۲/STAT۳ and elevated PPARα levels. PPARα lowered TGFβ۱-promoted fibroblastic proliferation and stimulated SIRT۱-mediated HMGB۱ deacetylation. Hence, HMGB۱ repression prevented caspase-۳-provoked apoptosis and enhanced the antioxidant role of AMPK/Nrf۲/HO-۱. Jointly, AMPK released ATF۳, which consequently stopped TLR۴/MyD۸۸/NF-kB-associated inflammatory cascade.Conclusion: NAFT may alleviate inflammation, oxidative stress, apoptosis, and fibrosis in ALI by activating the PPARα/SIRT۱/ATF۳ pathway. Moreover, NAFT may enhance DEXA treatment, particularly in resistant ALI patients.

کلیدواژه ها:

Acute lung injury ، ATF۳ ، Lipopolysaccharides ، Naftidrofuryl ، PPAR alpha ، SIRT۱