Hypoxia

Insufficient supply of oxygen to target tissues. Since most cells in the body rely on oxidative metabolism for the majority of their energetic needs, an inadequate supply of oxygen will cause a drop in cellular functions and will eventually cause them to die. Hypoxia co-occurs with inflammation both as a cause and as a consequence. Hypoxic injury to cells can trigger the inflammatory response, and inflammation can create parenchymal hypoxia trough accumulation of oxygen-consuming leukocytes and fluid in the surrounding ECM. Hypoxia is also a signal for macrophage-activation, which might be part of the reason why inflammatory processes tends to create such an environment around the affected tissues. Cells that don’tget enough oxygen switch on a different set of metabolic programs to meet their needs, which leaves molecular traces in the affected tissues. The most studied of these is hypoxia inducible factor 1-alpha (HIF-1a), which is considered a master regulator that orchestrates the cellular response to hypoxia. Another one is lactic acid, or lactate, which are products of non-oxidative metabolism of pyruvate, that gets up-regulated with hypoxic stress, it is sometimes measured indirectly by lowered pH. Hypoxia is the most powerful stimulus for the body to form new blood-vessels to penetrate further into hypoxic tissues, a process termed neovascularisation.

Supporting Evidence

• Inflammation creates an hypoxic environment¹⁾https://portlandpress.com/biochemist/article/39/4/34/475/Hypoxia-and-inflammation²⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206755/
• Hypoxia affects macrophage-function and survival.³⁾https://www.jimmunol.org/content/jimmunol/175/10/6257.full.pdf⁴⁾https://www.ncbi.nlm.nih.gov/pubmed/17416447
• There are associations between HIF-1a and hyperplasia for a number of different diseases.⁵⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944022/⁶⁾https://www.sciencedirect.com/science/article/pii/S0741521413005508⁷⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901746/

Conflicting Evidence

• Increasing levels of extracellular lactate might be a mechanism for cells to shunt energy to leukocytes.⁸⁾https://www.ncbi.nlm.nih.gov/pubmed/8436827⁹⁾https://www.ncbi.nlm.nih.gov/pubmed/10774612
• Increased rather than decreased oxygen-tension might be involved in the pathogenesis of DDD.¹⁰⁾https://www.spandidos-publications.com/10.3892/ijmm.2018.3523?text=fulltext
• Some tissues are naturally more hypoxic than others such as articular cartilage.¹¹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989071/

Association with Disease

• Increased levels of extracellular levels of lactate is a consistent finding in MPS.¹²⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062547/
• Doppler ultrasound shows retrograde blood-flow in diastole in focal MPS.¹³⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774893/
• Increased resistance to blood-flow in focal MPS.¹⁴⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039775/
• HIF-1a is up-regulated in RA and OA synovial tissue, and in TP tendons (including tendon-tears).¹⁵⁾https://www.jimmunol.org/content/jimmunol/175/10/6257.full.pdf¹⁶⁾https://www.sciencedirect.com/science/article/pii/S2255502116300505¹⁷⁾https://www.ncbi.nlm.nih.gov/pubmed/31093655¹⁸⁾https://pubmed.ncbi.nlm.nih.gov/20190320/
• Hypoxia is related to inflammation, apoptosis and an ECM-profile with increased collagen-III in TP:¹⁹⁾https://ard.bmj.com/content/71/2/302
• The oxygen-tension in RA synovial tissue has been shown to drop down to 0.²⁰⁾https://onlinelibrary.wiley.com/doi/abs/10.1002/art.1780130606
• Decreased pH in intervertebral discs may be connected to degeneration and pain.²¹⁾https://www.ncbi.nlm.nih.gov/pubmed/30478330
• HIF-1a is significantly up-regulated in human AS-tissue compared with control.²²⁾https://www.sciencedirect.com/science/article/pii/S0741521410013443