Jie Zhao,1,* Yuanyuan Ji,2,* Baozhu Li,3,* Ke Yang,1 Qi Sun,1 Tao Ma,3 Keliang Xie1 

1Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Tao Ma, Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, People’s Republic of China, Tel +86 13702172328, Email taoma@tmu.edu.cn Keliang Xie, Department of Critical Care Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, People’s Republic of China, Tel +8615332112099, Email xiekeliang2009@hotmail.com

Background: Hypercapnia, an Acute Respiratory Distress Syndrome (ARDS) complication after pulmonary sepsis, remains enigmatic in terms of its immunological mechanisms. Our study was designed to compare initial values and longitudinal changes in cellular composition and inflammatory biomarkers between pneumonia sepsis-induced ARDS patients without hypercapnia and hypercapnia patients.
Methods: Between Dec 2022-Apr 2023, we prospectively studied 61 severe pneumonia patients. Eleven non-sepsis pneumonia patients were controls; 50 patients with pulmonary sepsis met ARDS criteria, 26 among them developed hypercapnia. We collected clinical data, respiratory parameters, peripheral blood mononuclear cells (PBMCs), and bronchoalveolar lavage fluid (BALF) at Day 1 and Day 7 post-intubation. Single-cell RNA sequencing (ScRNA-seq) was performed between selected hypercapnia and non-hypercapnia patients to characterize immune and cellular profiles. Specimens were analyzed via flow cytometry and cytokine panel.
Results: By compiling clinical data and specimens, we found that hypercapnia patients with ARDS had poorer outcomes and higher mortality. At day 1, ScRNA-seq and cytometric analysis revealed increase in monocytes and activation of cytokine storm genes with elevated interleukin (IL) − 1β, IL-12p40, and IL-23 in peripheral blood. In hypercapnia patients, percentage of CD14+CD16- classical monocyte and concentrations of IL-12p40 and IL-23 increased from day 1 to day 7 in both circulation and airways. However, these alterations of cellular phenotype and cytokine decreased during seven-treatment period in non-hypercapnia patients.
Conclusion: We offer novel perspectives on monocyte-centered clusters and associated biomarkers, which play a pivotal role in driving hypercapnia after pulmonary sepsis-induced ARDS. Our study provides fresh insights into the immunological mechanisms underlying hypercapnia in ARDS, laying the foundation for useful therapeutic targets to improve patient outcomes.

Keywords: hypercapnia, pulmonary sepsis-induced ARDS, monocyte, cytokine storm, chemokine