The Tissue Response to Hypoxia: How Therapeutic Carbon Dioxide Moves the Response toward Homeostasis and Away from...

Sustained tissue hypoxia is associated with many pathophysiological conditions, including chronic inflammation, chronic wounds, slow-healing fractures, microvascular complications of diabetes, and metastatic spread of tumors. This extended deficiency of oxygen (O₂) in the tissue sets creates a microenvironment that supports inflammation and initiates cell survival paradigms. Elevating tissue carbon dioxide levels (CO₂) pushes the tissue environment toward "thrive mode," bringing increased blood flow, added O₂, reduced inflammation, and enhanced angiogenesis. This review presents the science supporting the clinical benefits observed with the administration of therapeutic CO₂. It also presents the current knowledge regarding the cellular and molecular mechanisms responsible for the biological effects of CO₂ therapy. The most notable findings of the review include (a) CO₂ activates angiogenesis not mediated by hypoxia-inducible factor 1a, (b) CO₂ is strongly anti-inflammatory, (c) CO₂ inhibits tumor growth and metastasis, and (d) CO₂ can stimulate the same pathways as exercise and thereby, acts as a critical mediator in the biological response of skeletal muscle to tissue hypoxia.