Kynurenic acid modulates inflammatory responses and disease severity in Streptococcus pneumoniae-induced ARDS 4553

Abstract Description Acute Respiratory Distress Syndrome (ARDS) is a severe inflammatory condition marked by oxidative stress and fluid buildup leading to hypoxia and sepsis. Recently, there has been increased attention due to the COVID-19 pandemic and severe hyper-inflammation. Recent findings indicate elevated kynurenine levels, a tryptophan metabolite, in the serum of SARS-CoV-2 patients. The kynurenine pathway produces metabolites, including kynurenic acid (KYNA), which influences immune responses via aryl hydrocarbon receptor (AhR) signaling. While KYNA is known for its anti-inflammatory effects, its role in ARDS is poorly understood. This study posits that KYNA worsens ARDS severity by enhancing inflammation. Employing a mouse model of Streptococcus pneumoniae-induced ARDS, we administered KYNA at 100 mg/kg daily via intraperitoneal injection and evaluated lung function, immune cell profiles, and cytokine levels after 48 hours. Our results revealed that KYNA treatment led to deteriorated pulmonary function, decreased neutrophil infiltration, and increased CD8+ T cells and AhR expression in the lungs. KYNA also raised pro-inflammatory cytokines TNFα and IL-1β in bronchoalveolar lavage fluid (BALF), potentially initiating a feedback loop that exacerbates inflammation. These findings suggest that KYNA accelerates ARDS progression via AhR activation and pro-inflammatory pathway enhancement, highlighting the need for further research into novel targets for therapeutic strategies for ARDS. Funding Sources Supported by NIH R00GM147910 to KW Topic Categories Immune Mechanisms of Human Disease (HUM)