Anti-inflammatory potential of the CISACN adduct in LPS-induced murine models

Acute lung injury (ALI) is characterized by a severe inflammatory response that triggers pulmonary edema, reduced lung compliance, and hypoxemic respiratory failure. To date, there is no effective standard pharmacotherapy for this condition. Recent studies have demonstrated that the Morita-Baylis-Hillman adduct (CISACN) exhibits anti-inflammatory activities in models of asthma and allergic rhinitis, alongside antitumor and antimalarial properties. It also presents low toxicity, low cytotoxicity, and good oral availability. Therefore, this study aimed to investigate the anti-inflammatory activity of the CISACN adduct in a lipopolysaccharide (LPS)-induced ALI model. BALB/c mice were challenged by nasal instillation with LPS and orally treated with CISACN (6.25, 12.5, or 25 mg/kg). Twenty-four hours later, bronchoalveolar lavage fluid (BALF), serum, and lung tissue were collected. Treatment with CISACN, primarily at a dose of 12.5 mg/kg, significantly reduced lung inflammation, as evidenced by decreased cell migration, levels of TNF-α, IL-1β, and IL-6, as well as reduced protein exudate in BALF. Additionally, it decreased serum TNF-α levels and attenuated histopathological alterations in the lung, such as edema, inflammatory cell infiltration, and hemorrhage. The anti-inflammatory effect of CISACN was related to its high energy and affinity with TLR4/p38 MAPK molecules, as evidenced by an in silico approach and confirmed by in vitro analysis, which showed inhibition of p38 MAPK activity. Therefore, this study highlights the anti-inflammatory potential of CISACN by inhibiting a key inflammatory pathway, identifying it as a promising agent for treating inflammatory processes.