Chronic Diseases as Barriers to Oxygen Delivery: A Unifying Hypothesis of Tissue Reoxygenation Therapy

  • G. A. PerdrizetEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 977)


Modern medical practice has resulted in the accumulation of a growing number of incurable chronic diseases, many of which are inflammatory in nature. Inflammation establishes a hypoxic microenvironment within tissues, a condition of inflammatory hypoxia (IH). Tissues thus affected become severely compromised, are unable to elicit adaptive responses and eventually develop fibrosis and fixed microvascular deficits. Previous work has demonstrated that tissue hypoxia exits even within the simple human model of self-resolving inflammation, the tuberculin reaction. Failed resolution of IH establishes a vicious cycle within tissues that perpetuates tissue hypoxia and resists standard drug therapies. Diseases such as sepsis, chronic cutaneous wounds, kidney disease, traumatic brain injury, solid tumors, inflammatory bowel disease, and chronic bacterial infections (urinary tract infection, cystic fibrosis) are tissue specific manifestations of chronic IH. Successful reversal of IH, through tissue re-oxygenation therapy (TROT), will break this vicious cycle and restore tissue homeostasis. The examples of solid tumors and inflammatory bowel disease are presented to illustrate a theoretical framework to support this hypothesis. Re-oxygenation of compromised tissues must occur before successful treatment of these diverse chronic diseases can be expected.


Chronic inflammation Hypoxia Hyperbaric oxygen Oxygen therapy Chronic disease 



Supported, in part, by the Ted and Michelle Gurnee Endowed Chair in Translational Research, Dept. of Emergency Medicine, UCSD, San Diego, CA.


  1. 1.
    Ward BW, Schiller JS, Goodman RA (2014) Multiple chronic conditions among US adults: a 2012 update. Prev Chronic Dis 11:E62PubMedPubMedCentralGoogle Scholar
  2. 2.
    Pawelec G, Goldeck D, Derhovanessian E (2014) Inflammation, ageing and chronic disease. Curr Opin Immunol 29:23–28CrossRefPubMedGoogle Scholar
  3. 3.
    Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hunt TK, Zederfeldt B, Goldstick TK (1969) Oxygen and healing. Am J Surg 118:521–525CrossRefPubMedGoogle Scholar
  5. 5.
    Abbot NC, Beck JS, Carnochan FM, Lowe JG, Gibbs JH (1992) Circulatory adaptation to the increased metabolism in the skin at the site of the tuberculin reaction. Int J Microcirc Clin Exp Sponsored Eur Soc Microcirc 11:383–401Google Scholar
  6. 6.
    Biddlestone J, Bandarra D, Rocha S (2015) The role of hypoxia in inflammatory disease (review). Int J Mol Med 35:859–869PubMedPubMedCentralGoogle Scholar
  7. 7.
    Newton DJ, Harrison DK, McCollum PT (1996) Oxygen extraction rates in inflamed human skin using the tuberculin reaction as a model. Int J Microcirc Clin Exp Sponsored Eur Soc Microcirc 16:118–123CrossRefGoogle Scholar
  8. 8.
    Abbot NC, Beck JS, Harrison DK, Wilson SB (1993) Dynamic thermographic imaging for estimation of regional perfusion in the tuberculin reaction in healthy adults. J Immunol Methods 162:97–107CrossRefPubMedGoogle Scholar
  9. 9.
    Harrison DK, Abbot NC, Carnochan FM, Beck JS, James PB, McCollum PT (1994) Protective regulation of oxygen uptake as a result of reduced oxygen extraction during chronic inflammation. Adv Exp Med Biol 345:789–796CrossRefPubMedGoogle Scholar
  10. 10.
    Abbot NC, Beck JS, Carnochan FM, Gibbs JH, Harrison DK et al (1985) 1994. Effect of hyperoxia at 1 and 2 ATA on hypoxia and hypercapnia in human skin during experimental inflammation. J Appl Physiol 77:767–773Google Scholar
  11. 11.
    Ince C (2015) Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 19(Suppl 3):S8PubMedPubMedCentralGoogle Scholar
  12. 12.
    Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol 543:39–55CrossRefPubMedGoogle Scholar
  13. 13.
    Fink MP (2015) Cytopathic hypoxia and sepsis: is mitochondrial dysfunction pathophysiologically important or just an epiphenomenon. Pediatr Crit Care Med 16:89–91CrossRefPubMedGoogle Scholar
  14. 14.
    Pinsky MR (1994) Beyond global oxygen supply-demand relations: in search of measures of dysoxia. Intensive Care Med 20:1–3CrossRefPubMedGoogle Scholar
  15. 15.
    Haase N, Perner A (2011) Central venous oxygen saturation in septic shock--a marker of cardiac output, microvascular shunting and/or dysoxia? Crit Care 15:184CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC (1953) The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26:638–648CrossRefPubMedGoogle Scholar
  17. 17.
    Fabrikant JI, Wisseman CL 3rd, Vitak MJ (1969) The kinetics of cellular proliferation in normal and malignant tissues II. An in vitro method for incorporation of tritiated thymidine in human tissues. Radiology 92:1309–1320CrossRefPubMedGoogle Scholar
  18. 18.
    Overgaard J (2011) Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis. Radiother Oncol 100:22–32CrossRefPubMedGoogle Scholar
  19. 19.
    Moen I, Tronstad KJ, Kolmannskog O, Salvesen GS, Reed RK, Stuhr LE (2009) Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma. BMC Cancer 9:446CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Peng HS, Liao MB, Zhang MY, Xie Y, Xu L et al (2014) Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells. PLoS One 9:e100814CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hatfield SM, Kjaergaard J, Lukashev D, Schreiber TH, Belikoff B et al (2015) Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7:277ra30CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hatfield SM, Kjaergaard J, Lukashev D, Belikoff B, Schreiber TH et al (2014) Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1alpha-dependent and extracellular adenosine-mediated tumor protection. J Mol Med (Berl) 92:1283–1292CrossRefGoogle Scholar
  23. 23.
    Dulai PS, Gleeson MW, Taylor D, Holubar SD, Buckey JC, Siegel CA (2014) Systematic review: the safety and efficacy of hyperbaric oxygen therapy for inflammatory bowel disease. Aliment Pharmacol Ther 39:1266–1275CrossRefPubMedGoogle Scholar
  24. 24.
    Weisz G, Lavy A, Adir Y, Melamed Y, Rubin D et al (1997) Modification of in vivo and in vitro TNF-alpha, IL-1, and IL-6 secretion by circulating monocytes during hyperbaric oxygen treatment in patients with perianal Crohn’s disease. J Clin Immunol 17:154–159CrossRefPubMedGoogle Scholar
  25. 25.
    Rossignol DA (2012) Hyperbaric oxygen treatment for inflammatory bowel disease: a systematic review and analysis. Med Gas Res 2:6CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Nyabanga CT, Kulkarni G, Shen B (2015) Hyperbaric oxygen therapy for chronic antibiotic-refractory ischemic pouchitis. Gastroenterol Rep (Oxf). doi: 10.1093/gastro/gov038 Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Emergency MedicineCenter for Wound Healing and Hyperbaric Medicine, UCSDSan DiegoUSA

Personalised recommendations