Negative Feedback Mechanism In Tissue During Hypoxia: Homeostasis

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In this report what I am going to talk about is basically Negative feedback mechanism during Hypoxia. The reason I am going to talk about this topic is that many things happen in our body but we don’t even know anything about them, so we have to learn several things about our own body like how to protect ourselves from illnesses and how to get vitamins into our body. As a student or anyone what do we know about Hypoxia and Negative feedback mechanism? What can a Negative feedback mechanism do to Hypoxia when this condition (Hypoxia) happens in our body? What are the types and symptoms of Hypoxia? Can Hypoxia be prevented? So let me define these two terms and answer these questions.

Hypoxia is the deficiency in the amount of the oxygen reaching the tissues that need oxygen to maintain the cells healthy or Hypoxia is a condition where tissues are not oxygenated sufficiently and suitably because of an insufficient concentration of oxygen in the blood.

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What about the other term a Negative feedback mechanism? So a Negative feedback mechanism or a balancing feedback mechanism is a reaction that causes a limited decrease in functions. It happens in response to some kind of stimulus. It always leads to stability to the systems of the body, so we can say that it is a regulatory mechanism that results: 1- Arrest of stimulus or change. 2- Reduce effects. 3- A negative change to initial effect.

The biological systems of the body work on a mechanism of inputs and outputs, each caused by and causing a specific event. A feedback loop is an occurrence wherein the output of a system amplifies the system (Positive Feedback) or inhibits the system (Negative Feedback). Feedback loops are important because they allow living organisms to maintain homeostasis. Homeostasis is the mechanism that empowers us to keep our internal environment constant.

Hypoxia has 4 types: (hypoxic, hypemic, stagnant, and histotoxic) Hypoxia. The most common hypoxia symptoms are: changing the color of skin from blue to cherry red, cough, fast heart rate, slow heart rate, rapid breathing, sweating, shortness of breath, and etc. most people will die within ten minutes of total oxygen deprivation (Hypoxia). When your blood doesn’t carry enough oxygen to your tissues to meet your body’s requirements it causes Hypoxia.

Hypoxia can be prevented by taking your medicine regularly, staying active, keeping your Asthma under control, and working with your doctor to set a plan for you. Oxygen therapy as a treatment is used to help you breathe easier. You may need medicines to treat the cause of your Hypoxia as well.

Hypoxia in a critical threshold restricts the function of organs, tissues, and cells. It induces a great number of changes in the metabolites, proteins, and enzymes involved in vital biological functions resulting in clinical obstacle. Acute Hypoxia results in depletion of ATP in cells that triggers a switch to anaerobic glycolysis.

Hypoxia may affect every part of the body (generalized Hypoxia), or a specific organ or area of the body (tissue Hypoxia). In tissue Hypoxia, Hypoxia deprives the ETC (electron transport chain) of sufficient oxygen, decreasing the rate of ETC and ATP production. When ATP levels fall, glycolysis increases and, in the absence of oxygen, will produce lactate (lactic acidosis). Anaerobic glycolysis is not able to meet the demand of most tissues for ATP, especially in highly aerobic tissues like cardiac muscle and nerves. The most affective organs by Hypoxia are the brain, the liver, and the heart.

When Hypoxia is severe, irreversible damage can start within four minutes of the onset. Coma, seizures, and death may occur in severe cases. Chronic and milder Hypoxia can cause damage to the major organs of the body as well. In the next pages I will talk more about Negative feedback mechanism during Hypoxia in more details, how a Negative feedback mechanism affects the tissues. I will explain it very accurately, and give examples about this topic that I mentioned before.


In this page and the next pages I will talk about the Negative feedback mechanism during Hypoxia in two clear parts.

Part 1: Homeostasis.

Homeostasis is the ability to maintain relative stability of the body and function, even serious changes may happen in the external environment or in one part of the body. A line of control mechanisms, some function at the organ or tissue level and other controlled, maintain Homeostasis. The most central homeostasis controls are the nervous and endocrine systems.

Mental and physical stresses, disease, and injury constantly challenge us and they can intervene with homeostasis. When the body misses its homeostasis, it might plunge out of control, into illness, dysfunction and even death.

Maintaining Homeostasis

In order to maintain homeostasis, the body reacts to irregular change (induced by a toxic stuff), biological organism, or any other things) and makes certain adjustments to oppose the change (a defense mechanism). The main components responsible for the maintenance of homeostasis involve:

  • Stimulus- a change in the environment which causes a response, such as loss of blood, an irritant, or presence of a new and foreign chemical.
  • Receptor- the site within the body that detects and receives the stimulus, senses the change from normal, and sends signals to the control center.
  • Control center- or the integrating center receives information from the receptors and initiates the response to maintain homeostasis. The point at which the signals are received, analyzed, and an appropriate response is determined.
  • Effector- the body site where a response is produced, which opposes the initial stimulus and thus tries to maintain homeostasis.
  • Feedback mechanism- approaches by which the body regulates the level of response that has been obtained. A Negative feedback depresses the stimulus to reduce the effector response, while a Positive feedback has the effect of increasing the effector response.

Example: Reaction to a Toxin

An example of a homeostasis mechanism can be explained by the body’s reaction to a toxin that causes Anemia and Hypoxia (low tissue oxygen) (figure 1). The action of making RBC (erythropoiesis) is controlled mostly by the hormone, erythropoietin. When the body moves into a state of Hypoxia (the stimulus), it encourages the hemeprotein (the receptor) that signals the kidney to compose erythropoietin (the effector). That, in turn, stimulates the bone marrow to increase RBC and hemoglobin, increasing the ability of blood to transport oxygen and thus increases the tissue oxygen levels in the blood and other tissues. This increase in tissue oxygen levels acts to suppress more erythropoietin synthesis (feedback mechanism). In this example, cells and chemicals work together to produce changes that could either restore homeostasis or disrupt homeostasis. Toxic stuffs that destroy the kidney can intervene with the production of erythropoietin or toxic stuffs that destroy the bone marrow can inhibit the production of RBC.

Part 2: Lack of Hypoxic Response in Uterine Leiomyomas despite Severe Tissue Hypoxia.

Hypoxia is currently established as an important factor affecting the pathophysiology of malignant growth. Among other effects, hypoxia moderates the expression of a lot of genes through the induction of hypoxia-inducible transcription factors. This gene expression favors angiogenesis (the formation of blood vessels), cell survival, an invasive/metastatic phenotype, and resistance to anticancer therapies. Because benign tumors do not show these traits, one may expect entities to be neither hypoxic nor to prompt the genetic hypoxia response program.

Clinical investigation of different tumor entities, such as head and neck cancer, cervical cancer, and soft tissue sarcoma (sarcoma= a malignant tumor of connective tissue or nonepithelial tissue) discovered a correlation between tumor oxygenation and prognosis irrespective of the treatment modality. Those results achieved great attentions in the field of cancer research and therapy because they directed a clinically new applicable universal indicator of tumor aggressiveness and paved the way for more insights into the pathobiology of malignant disease. The idea of tumor hypoxia handing an obstacle to success of some forms of chemotherapy and radiotherapy changed to the idea of tumor hypoxia as a vital driving force in malignant progression. More findings indicated that hypoxia as an inherent outcome of unregulated tissue growth promotes local attack, intravasation (entrance of a foreign body into a blood vessel), and ultimately metastatic spread at 3 levels and this happens in a collective manner: 1- on the proteome/metabolome level through adaptive gene expression; 2- genome/epigenome level by raising genomic and epigenomic instability; 3- on the level of cell populations by selection and clonal extension according to phenotype fitness.

Hypoxia-induced changes in gene expression are organized largely by the hypoxia-inducible factor-1 (HIF-1) and (HIF-2). The effects of HIF activation, which contribute to increased malignancy, involve modulation of glucose metabolism through increased cellular glucose uptake via glucose transporter-1 (GLUT-1) and increased glycolysis by up-regulation of important glycolytic enzymes, increased proton-extrusion capacity by lots of expression of carbonic anhydrase IX (CA IX), increased angiogenesis by up-regulation of vascular endothelial development factor, and the activation of the c-MET/HGF system determined by cell proliferation, cell dissociation, migration, and apoptosis protection (apoptosis= natural process in which a cell disintegrates after reaching a specific age or because of poor cell health).

Infrequent uterine leiomyomas are the most frequent benign tumors in women, increasing in 40% to 70% of all women in their next reproductive years. Single or multiple leiomyomas originate mainly from smooth cells of the myometrium. Despite long phases of autonomous growth, which might result in large tumours, uterine leiomyomas do not exhibit clinically significant tendency for invasion or metastasis. Thus these lesions don’t expect to be hypoxic and element of transcriptional response evoked by HIFs should be inactive.

Increasing uterine leiomyomas in premenopausal women show highly low pO2 values.

A central regulator of anabolic processes and cell growth in eukaryotic cells are the serine/threonine kinase mammalian target of rapamycin (mTOR). Activation of mTOR is the last common pathway for growth factors signaling through receptor tyrosine kinases and downstream phosphatidylinositol-3 kinase (PI3K) and rat sarcoma (RAS) pathways. mTOR matches these stimulatory signals to nutritious availability in the microenvironment. It shows that oxygen availability plays an important and central role in this regulation.

Repression of mTOR signaling under hypoxia can be a key and important element in a feedback mechanism that causes an adapted bioenergetics status in the hypoxic microenvironment of leiomyomas. Hypoxia activates the TSC-1/2 (hamartin/tuberin) complex via sensing proteins, which may comprise AMP-activated protein kinase (AMPK) or regulated in development and DNA damage responses 1 (REDD1). The TSC-1/TSC-2 complex is a GTPase activator for the small GTPase RAS homologue enriched in brain (Rheb), promoting Rheb deactivation (a common and usual principle in the regulation of G protein-coupled signaling). Because mTOR is influenced by stimulation of Rheb or mTOR is dependent on stimulation by Rheb, hypoxia might down-regulate its activity via this pathway. In addition to being a crucial event leading to reduced cell growth, inhibition of mTOR has also been shown to lead to the direct down-regulation of HIF-1a at the level of mRNA translation or protein stability.

Negative feedback mechanisms on HIF-1a signaling under chronic hypoxia with special emphasis on mTOR. In nomoxia (left, white background), HIF-1a protein synthesis is up-regulated by growth factor signaling via PI3K/AKT and RAS/extracellular signal-regulated kinase (ERK) pathways through inhibition of the TSC-1/TSC-2 complex and following activation of mTOR by GTP-bound Rheb. mTOR stimulates anabolic processes at many levels as well. Hypoxia (right, light gray background) activates the TSC-1/TSC-2 complex by activating REDD1 and AMPK. Both proteins increase the GTPase activity of Rheb, leading to its conversion to the GDP-bound state, a change in protein conformation and suppression of mTOR signaling. Activation of TSC-1/TSC-2 by hypoxia may be partly HIF-1a dependent (via the transactivation of REDD1) and partly HIF-1a independent. The latter pathway includes the phosphorylation of AMPK by LKB1 in the presence of AMP and perhaps a direct effect of hypoxia on REDD1 activity via undefined and unspecific upstream signaling processes. HIF-1a promotes its own degradation as well by induction of prolyl hydroxylases (PHDs), which-despite being most effective when O2 levels are normal or high- remain partly active under hypoxia. Gray level gradients match with oxygen gradients, with the darkest areas representing the most severely hypoxic state.


In this report we learnt many things about Hypoxia and negative feedback and negative feedback during hypoxia. We learnt that hypoxia is a low oxygen concentration in the blood, or hypoxia is defined as the inadequate oxygen delivery to the tissue cells. There were 4 types of hypoxia (hypoxic, hypemic, stagnant, and histotoxic) hypoxia. Changing the color, cough, and shortness of breathing are the most common symptoms of Hypoxia. When the cells don’t get enough oxygen it causes something that is called Hypoxia, so the whole cellular factory can be damaged. Negative feedback mechanisms are designed to maintain homeostasis.

When we eat a toxic stuff, it may cause hypoxia. The production of erythropoiesis (RBC) is determined by a hormone named erythropoietin. We learnt that hypoxia means low O2 tensions so hypoxia becomes the stimulus. It activates the receptor that sends the signals to the kidney to produce erythropoietin (the effector) which stimulates the bone marrow to increase red blood cells (RBC) and hemoglobin, so it caused increasing in RBCs because already hypoxia caused decreasing in RBCs. Here the negative feedback mechanism regulated the degree of the response, a negative feedback depressed the stimulus to reduce the effector response.

In other words, the evidence has been presented that despite the presence of extreme hypoxia, the HIF system is inactive in benign uterine leiomyomas. A negative feedback mechanism on HIF-1a signaling under hypoxia with special emphasis on mTOR happens.

To more information about this topic, we can use some other books and sites like; (“Hypoxia translation in progress” book), (“Hypoxia and the circulation book”).


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