Nezulcitinib (TD-0903), an inhaled JAK inhibitor reduces ConA-induced lung inflammation and lung injury in mice

Background: Elevated cytokine signaling in response to acute infection in viral-ALI/ARDS or alloimmune recognition in lung transplant leads to tissue injury. IFNγ signals through the JAK/STAT pathway and is elevated in lungs of patients with COVID-19 and lung transplant rejection. An inhaled JAK inhibitor may reduce pulmonary inflammation and injury by disrupting IFNγ signaling while minimizing systemic immunosuppression. Concanavilin A (ConA) is a lectin that can directly damage epithelial cells and induce release of IFNγ from lymphocytes. Objectives: To demonstrate that the inhaled pan-JAK inhibitor, nezulcitinib, blocks ConA-induced lung inflammation in mice. Methods: Nezulcitinib (0.6 and 2 mg/kg) was administered to mice by oropharyngeal aspiration (OA) 60 min before and 10-hours after an OA administration of ConA. Lung CXCR3 chemokines were measured 8-hours, BALF neutrophils 48-hours, and lung histopathology and pSTAT1 staining 24-hours after ConA. Results: Nezulcitinib reduced ConA-induced lung CXCR3 chemokines (≥70-100% inhibition for CXCL9, CXCL10, and CXCL11), BALF neutrophils (~97%), and parenchymal pSTAT1 staining. The ConA-induced histological signs of ALI including interstitial inflammation, peribronchial/perivascular edema, and neutrophil influx were also reduced. Nezulcitinib lung concentrations 8-hours after OA administration were sufficient to inhibit JAK-STAT signaling. Conclusion: Nezulcitinib blocks ConA-induced inflammation in mouse lung demonstrating therapeutic potential for lung allograft dysfunction and ALI/ARDS.