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

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 (O(2)) in the tissue sets creates a microenvironment that supports inflammation and initiates cell survival paradigms. Elevating tissue carbon dioxide levels (CO(2)) pushes the tissue environment toward “thrive mode,” bringing increased blood flow, added O(2), reduced inflammation, and enhanced angiogenesis. This review presents the science supporting the clinical benefits observed with the administration of therapeutic CO(2). It also presents the current knowledge regarding the cellular and molecular mechanisms responsible for the biological effects of CO(2) therapy. The most notable findings of the review include (a) CO(2) activates angiogenesis not mediated by hypoxia-inducible factor 1a, (b) CO(2) is strongly anti-inflammatory, (c) CO(2) inhibits tumor growth and metastasis, and (d) CO(2) can stimulate the same pathways as exercise and thereby, acts as a critical mediator in the biological response of skeletal muscle to tissue hypoxia.