Molecular mechanisms of CO2-sensing and their significance during healing of intestinal anastomoses

• Applicant: Dr. Moritz Johannes Strowitzki
• Subject Area: General and Visceral Surgery ; Anatomy and Physiology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532010140

In surgery, high CO2 concentrations are utilized to induce a capnoperitoneum within the patient’s abdomen, enabling sufficient space and vision during minimal-invasive procedures. During complex and long-lasting “open” abdominal operations, perioperative CO2 levels increase within the patients’ blood stream. Although these surgical procedures are considered as safe, severe complications due to impaired healing of intestinal anastomoses (anastomotic leakages, AL) occur in 7% of all patients. During the development of AL, specialized immune cells, such as macrophages, play a significant role. Own previous work suggests that high CO2 levels mitigate immune cell function during inflammatory responses and CO2 is thus considered anti-inflammatory. Both CO2 and CO2-adaptive signaling pathways profoundly alter macrophage differentiation and activation through intracellular pH changes and thereby attenuate the migratory potential of macrophages. The macrophage-specific expression and enzyme activity of carbonic anhydrase (CA) 2, which catalyzes the reaction of CO2 to HCO3- and H+ and thereby affects intracellular pH level, is crucially involved during CO2-driven effects on macrophage differentiation and activation. Preliminary data of the applicant suggest, that pharmacologic CA2 inhibition elicits direct effects on both function and CO2-sensitivity of macrophages, which could indirectly alter AL rates. Utilizing established small animal models a potential effect of different CO2 levels on healing of intestinal anastomoses will additionally be determined. Initial retrospective analysis of a prospective database showed that patients with high (systemic) CO2 levels (for example, patients with chronic lung diseases) have an increased risk developing AL. In matched patients suffering from AL, the applicant will further analyze whether different CO2 levels altered the cellular microenvironment within intestinal anastomoses and if distinct expression patterns of inflammatory and metabolic markers predict AL in these patients. Tissue biopsies of “leaking” colon anastomoses and corresponding healthy colon mucosa will be analyzed by immuno-histochemistry and molecular genetic approaches to correlate immune cell infiltration and expression patterns with the clinical course.Taken together, the present project will investigate novel molecular CO2-sensing mechanism and their effect on macrophage differentiation and activation. In addition, the effect of CO2 and CO2-adaptive signaling pathways on healing of intestinal anastomoses will be determined. Controlling perioperative CO2 levels or altering macrophage-specific CO2-sensitivity by pharmacologic CA-inhibition could represent an extremely cost-effective treatment option to improve healing of intestinal anastomoses, in particular in high-risk patients with chronic lung diseases.

• DFG Programme: Independent Junior Research Groups