Investigation of the protective effect of cilostazol on acute lung injury-mediated inflammation and in silico molecular modelling studies of inflammatory signalling pathway: a repurposing study.

Summary

In an LPS-induced rat ALI model, cilostazol bound multiple inflammatory proteins in silico and reduced oxidative stress, cytokines (IL-6, TNF-α), KL-6, LDH, MPO, CRP, NO, edema, vascular leakage, and inflammatory cell recruitment in vivo. It downregulated TNF-α, NF-κB, TLR4, and JAK/STAT3 mRNA and improved total lung capacity, supporting repurposing for ALI/ARDS.

Key Findings

• In silico docking predicted cilostazol binding to 10 inflammatory targets (PDK1, RAC1, PTK6, KDR/VEGFR2, EGFR, endothelin-1, caspase-3, TNF-α, NF-κB1/BTK, TLR/IRAK4) with affinities comparable to known inhibitors.
• In vivo, cilostazol reduced oxidative stress, pulmonary edema, vascular leakage, and inflammatory mediators (IL-6, TNF-α, NO, CRP, LDH, MPO, KL-6) and decreased inflammatory cell recruitment in LPS-induced ALI.
• Cilostazol downregulated mRNA expression of TNF-α, NF-κB, TLR4, and JAK/STAT3 and improved total lung capacity in rats.

Clinical Implications

Although preclinical, findings justify exploration of cilostazol as an adjunctive anti-inflammatory therapy for ALI/ARDS, with careful attention to bleeding risk and dosing. Clinical trials are needed to assess efficacy, safety, and patient selection.

Limitations

• Preclinical single-species LPS model; human efficacy and safety unknown
• Sample size, randomization/blinding, and dose–response details not reported in the abstract; docking does not prove target engagement

Future Directions

Validate across multiple ALI/ARDS models (e.g., ventilator-induced, acid aspiration), establish dose–response and pharmacokinetics, assess bleeding risks, and progress to phase 1/2 trials to evaluate safety and preliminary efficacy.