Responses to Hypoxia

Erythropoietin is a growth factor produced by interstitial cells of the kidney in response to hypoxia. Erythropoietin stimulates haematopoiesis in the bone marrow. Recombinant human erythropoietin is used to treat anemias, e.g. anemia caused by chronic renal failure and anemia in AIDS and cancer patients. 

Human erythropoietin is a glycoprotein of 166 amino acids (molecular mass about 34 kDa). Its amount in plasma can be measured by radioimmunoassay. It is the major regulator of human erythropoiesis. Erythropoietin is synthesized mainly by the kidney and is released in response to hypoxia into the bloodstream, in which it travels to the bone marrow. There it interacts with progenitors of red blood cells via a specific receptor. The receptor is a transmembrane protein consisting of two different subunits and a number of domains. It is not a tyrosine kinase, but it stimulates the activities of specific... 

Additionally, with chronic hypoxia, normal hemoglobin and hematocrit values may represent relative anemia.12 Increased red blood cell production is a physiologic response to hypoxia however, this response may be blunted in CF and may result in symptoms of anemia despite normal lab values. Abnormal bleeding may also be observed as a result of vitamin K malabsorption or antibiotic-associated depletion of gastrointestinal flora and vitamin K synthesis. 

Smatresk, N.J. 1986. Ventilatory and cardiac reflex responses to hypoxia and NaCN in Lepisosteus osseus, an air-breathing fish. Physiol. Zool. 59 385-397. 

Smatresk, N.J., M.L. Burleson, and S.Q. Azizi. 1986. Chemoreflexive responses to hypoxia and NaCN in longnose gar evidence for two chemoreceptor loci. Amer. Jour Physiol. 251(1,Part 2) R116-R125. 

Nakayama, K., et al., Siah2 regulates stability of prolyl-hydroxylases, controls HlFla abundance and modulates physiological responses to hypoxia. Cell, 2004, 117(7), 941-52. 

Diabetes is hypothesized to cause cardiac protein acetylation and the acetylation alters the protein function (Fig. 3b). Hypoxia-inducible factor-1 (HIFl) is a transcription factor found in mammalian cells cultured under reduced oxygen tension that plays an essential role in cellular and systemic homeostatic responses to hypoxia. Diabetes interferes with cellular response to hypoxia. In hyperglycemic conditions HIFl degradation is increased because of enhanced HIFl acetylation by... 

Benita Y, Kikuchi H, Smith AD et al (2009) An integrative genomics approach identifies hypoxia inducible factor-1 (HIF-1 )-target genes that form the core response to hypoxia. Nucleic Acids Res 37 4587-4602... 

Opioids depress respiration via the ji2-receptor at the level of the medulla and thereby increase PCO2. Opioids reduce respiration, an effect that is fatal in the case of overdose, by a dual action. The opioids decrease both the sensitivity of the medulla to carbon dioxide concentrations and the respiratory rate. Cardiovascular function and the response to hypoxia are not compromised. By contrast, tolerance to the respiratory depressant effects of the opioids does not appear to occur, while tolerance to the emetic effects of the opioids occurs upon repeated administration. The area postrema chemoreceptor trigger zone of the medulla mediates opioid-induced vomiting. 

Maintenance of red cell volume is critical to having an adequate oxygen supply to the tissues [10]. Healthy individuals finely balance erythropoiesis and erythrocyte loss and maintain constant hematocrit. The glycoprotein hormone erythropoietin is the principal controller of the homeostatic mechanism that links tissue oxygen delivery to red cell production. While hypothesized as early as 1863, unequivocal evidence of erythropoietin was first published in 1953. A few years later, scientists showed that animals subjected to bilateral nephrectomy were unable to mount an erythropoietin response to hypoxia. Indeed, the kidneys produce about 90% of circulating erythropoietin. 

Clinical pharmacology Erythropoietin is instrumental in the production of red cells from the erythroid tissues in the bone marrow. The majority of this hormone is produced in the kidney in response to hypoxia, with an additional 10% to 15% of synthesis occurring in the hver. Erythropoietin functions as a growth factor, stimulating the mitotic activity of the erythroid progenitor cells and early precursor cells. Chronic renal failure patients often manifest the sequelae of renal dysfunction, including anemia. Anemia in cancer patients may be related to the disease itself or the effect of concomitantly administered chemotherapeutic agents. 

The respiratory actions of the methylxanthines may not be confined to the airways, for they also strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm in patients with COPD. This effect on diaphragmatic performance—rather than an effect on the respiratory center—may account for theophylline s ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction. 

Grieshaber M, Hardewig I, Kreutzer U, Pcirtner H-0 (1994) Physiologial and metabolic responses to hypoxia in invertebrates. Rev Physiol Biochem Pharmacol 125 43-147... 

One of the major features of solid tumors and even small deposits of tumor tissue is deficiency in the level of oxygen, because of an inadequate vascular supply. The adenosine elevation in response to hypoxia is not exclusive to tumor tissues, but, in this context, the adenosine elevation is localized to the tumor microenvironment, since the surrounding tissue is normally oxygenated. Adenosine is generated mainly by two enzymatic systems intra- or extracellularly localized 5 -nucleoti-dases and cytoplasmic S-adenosylhomocysteine hydrolase. The processes of adenosine elimination in the cell involve reactions catalyzed by adenosine deaminase and adenosine kinase (Shryock and Belardinelli 1997) yielding inosine or 5 -AMP,... 

Hypoxia creates conditions that, on one hand, are conducive to the accumulation of extracellular adenosine and, on the other hand, stabilize hypoxia-inducible factors, such as HIF-1 a (Linden 2001 Sitkovsky et al. 2004 Fredholm 2003 Hockel and Vaupel 2001 Minchenko et al. 2002 Semenza 2000). HIF-1, the most important factor involved in the cellular response to hypoxia, has been extensively studied this last decade. However, despite the substantial number of investigations into HIF-1, many secrets about its function remain to be revealed. 

It has been specifically focused on responses to chronic hypoxia that involve adenosine-induced changes in the transcription regulator HIF-1 expression. In particular, it has been investigated the correlation between adenosine receptor stimulation and/or blockade and HIF-la expression modulation in hypoxia. It has been demonstrated that adenosine is able to increase HIF-la protein expression in response to hypoxia in a dose- and time-dependent manner in human melanoma, glioblastoma and tumor colon cells (Merighi et al. 2005,2006,2007). These results indicate that the cell surface A3 adenosine receptor transduces extracellular hypoxic signals into the cell interior. 

Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17(11) 3005-3015 Semenza GL (1999) Perspectives on oxygen sensing. Cell 98(3) 281-284 Semenza GL (2000) HIF-1 mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88(4) 1474-1480... 

The hypothesis that hypoxia receptors exist, and can be stimulated by vitamin E and agents in the body which have a structural similarity to the vitamin but which are not necessarily antioxidants, might be useful as a way of investigating the body s physiological and biochemical response to hypoxia. The mechanism of this response could also offer a pharmacological perspective in which new anti-hypoxia drugs could be generated. 

The cfos and cjun gene responses to hypoxia have not yet been evaluated in turtle liver cells, although they are likely to play roles at least as significant, if not more so, than in ischemic or... 

Yenkatachalam, M.A., and J.M. Weinberg (1993). Structural effects of intracellular amino acids during ATP depletion. In Surviving Hypoxia, pp. 473 -94, ed. J.R. Sutton, C.S. Houston and G. Coates. Burlington, Vt. Queen City Printers. Wang, G.L., and G.L. Semenza (1993). General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl. Acad. Sci. USA 90 4304-4308. 

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