V-domain Ig Suppressor of T cell Activation Expression During Hemorrhage or Sepsis-Induced Acute Respiratory Distress Syndrome: Insights From a Mouse Model

Abstract

Introduction

Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary condition with significant mortality, largely due to a lack of therapeutic interventions grounded in its molecular pathophysiology. Immune checkpoint regulators, such as the V-domain Ig Suppressor of T cell Activation (VISTA), may provide novel immunotherapeutic strategies for ARDS by modulating the immune response, a concept extensively explored in cancer and autoimmune diseases. Investigating VISTA in the context of ARDS could unveil new therapeutic avenues.

Methods

We used a mouse model of indirect ARDS by subjecting C57BL/6J mice to hemorrhage followed by cecal ligation and puncture. Systemic and localized inflammatory conditions were assessed using samples from blood, lung, and peritoneal fluid. Lung pathology was quantified by scoring hematoxylin and eosin-stained sections. Flow cytometry, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction analyses concentrated on macrophages, neutrophils, endothelial cells, and epithelial cells to elucidate VISTA expression patterns.

Results

Hemorrhage or cecal ligation and puncture–treated mice exhibited hallmark symptoms of indirect ARDS, including elevated levels of inflammatory cytokines and chemokines. Notably, VISTA expression was substantially upregulated on various cell types, including blood monocytes, lung macrophages, and both circulating and lung-infiltrating neutrophils, as well as on pulmonary epithelial cells and endothelial cells.

Conclusions

Our model replicates critical inflammatory and physiologic changes leading to ARDS, with the elevated expression of VISTA on immune and parenchymal cells suggesting its central involvement in lung injury. The findings propose VISTA as both a potential biomarker for lung damage and as a promising target for ARDS therapy.