Losartan as a Reproposing Therapeutic Agent in Acute Respiratory Distress Syndrome: Modulating Inflammatory Responses and Cytokine Production.

Abstract

Seeking a new drug has become a significant milestone in drug discovery. However, it might not be immediately used in urgent situations or during a pandemic. Acute Respiratory Distress Syndrome (ARDS) contributes to mild-to-severe symptoms in patients due to cytokine storms, leading to morbidity and mortality. Hypertension is recognized as an independent risk factor for the severity of ARDS regarding to both ACE Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) treatment, although the precise mechanism remains unclear. In this study, murine macrophage cell lines (RAW264.7) and alveolar epithelial type II-like cell lines (A549) were utilized to investigate the effect of Losartan (LOS). LOS attenuated nitric oxide production in a dose-dependent manner and collectively reduced intracellular reactive oxygen species (ROS) compared to Diclofenac under LPS-stimulation conditions. For ADRS-mimicking conditions, LPS-induced inflammatory A549 cells were performed to monitor the effect of LOS. The results showed that LOS exhibited a protective effect by increasing cell viability and decreasing intracellular ROS levels. Notably, a high dose of LOS increased intracellular ROS levels. Moreover, LOS treatment downregulated NF-kappaB activation and AT1R at the protein level. Correspondingly, proinflammatory mediator cytokines (TNF-alpha and IL-8) were downregulated, but not IL-6, during LOS treatment. Hence, LOS may provide substantial benefits to ARDS patients by modulating proinflammatory cytokine production through AT1R downregulation and NF-kappaB inactivation. The mechanistic insight into LOS's anti-inflammatory effect holds promise for reducing mortality rates among ARDS patients.