Relationship Between Hypoxia and Inflammation:

Chapter 4: Cellular Biology This chapter explores altered cellular and tissue biology, focusing on cellular adaptation, injury, manifestations of cellular injury, cellular death, aging, and the various types of cell death such as necrosis and apoptosis. Cellular adaptation allows cells to respond to physiological and pathological conditions, but severe or prolonged stressors can lead to cellular injury or death. Common sources of cell injury include lack of oxygen, free radicals, infections, inflammation, and metabolic derangements. Cellular aging also contributes to changes in structure and function. Bullet points Relationship between hypoxia and inflammation: ● Hypoxia (decreased oxygen delivery or ischemia) has been linked to inflammatory bowel disease, certain cancers, and infection ● Tumors adapt to low oxygen levels through mechanisms such as angiogenesis, increased glucose consumption, and promoting glycolysis Hypoxic injury induced by ischemia: ● Consequences of decreased oxygen delivery or ischemia with decreased ATP: ● Structural and physiologic changes are reversible if oxygen is delivered quickly, significant decreases in ATP result in cell death, mostly by necrosis ● Mitochondrial damage can result in changes in membrane permeability, loss of membrane potential, and decrease in ATP concentration ● Calcium ions play a critical role in cell injury, with increased release from intracellular stores and influx across the plasma membrane Hypoxia and Inflammation: ● Clinical conditions characterized by tissue hypoxia cause inflammatory changes ● Inflammatory diseases can lead to hypoxia Arteriosclerosis, thrombus, and consequences: ● Arteriosclerosis (narrowing of blood vessels) and thrombus (blood clots within vessels) can result in localized tissue ischemia ● Gradual arterial narrowing is better tolerated than acute anoxia caused by an acute obstruction or thrombus ● An acute obstruction in a coronary artery can result in a rapidly evolving myocardial infarction ● Progressive hypoxia typically results in myocardial adaptation, while acute anoxia leads to irreversible myocardial cell death Cellular responses to hypoxic injury: ● Within 1 minute after blood supply is interrupted, the heart becomes pale and dysfunctional, unable to contract normally ● Within 3 to 5 minutes, mitochondrial compromise occurs, resulting in insufficient ATP production ● Lack of ATP leads to a decrease in mitochondrial phosphorylation and insufficient ATP production, leading to a lack of contraction Anaerobic Metabolism and Ischemia ● Anaerobic metabolism generates ATP from glycogen when there is insufficient oxygen ● Glycogen stores depletion causes anaerobic metabolism to cease ● Reduction in ATP levels due to ischemia leads to failure of sodiumpotassium pump and sodium-calcium exchange mechanisms ● Sodium and calcium accumulate in the cell while potassium diffuses out ● Cellular swelling and ER dilation occur due to sodium and water freely entering the cell Effects of Hypoxia ● Ribosomes detach from the rough ER, reducing protein synthesis ● Persistent hypoxia leads to marked swelling of the entire cell Consequences of Continued Hypoxia ● Calcium accumulation within the cell leads to cell death as essential metabolic processes cease ● Influx of calcium activates enzymes triggering apoptosis ● Restoration of blood flow and oxygen can cause additional injury known as ischemia-reperfusion injury Mechanisms of Ischemia-Reperfusion Injury ● Oxidative stress: Reoxygenation generates reactive oxygen radicals that damage membranes and facilitate calcium overload ● Increased intracellular calcium concentration: Reperfusion results in calcium influx and mitochondrial permeability ● Inflammation: Ischemic injury promotes an inflammatory response ● Complement activation: Complement activation may worsen damage caused by reperfusion injury Pathogenesis of hypoxic injury ● Hypoxic injury occurs when cells are deprived of oxygen ● This can happen due to reduced blood flow (ischemia) or decreased oxygencarrying capacity of blood ● The lack of oxygen leads to the inability of the cell to generate energy through oxidative phosphorylation ● Without energy, cellular functions are impaired, leading to cell injury and potentially cell death Mechanisms of ischemia-reperfusion injury ● Ischemia-reperfusion injury occurs when blood flow to a tissue or organ is initially restricted (ischemia) and then restored (reperfusion) ● During ischemia, there is a lack of oxygen and nutrients in the tissues, leading to cellular damage ● When blood flow is restored, a burst of oxygen and inflammatory cells can cause additional damage to already compromised tissues ● The mechanisms of ischemia-reperfusion injury include oxidative stress, inflammation, and the activation of various cell death pathways Free radicals and oxidative stress ● Free radicals are reactive molecules with an unpaired electron ● They can cause damage to proteins, lipids, and carbohydrates within the cell membrane ● Oxidative stress occurs when there is an imbalance between the production of free radicals and the body's ability to detoxify them ● Reactive oxygen species (ROS) are a type of free radicals produced during cellular metabolism and energy generation ● Oxidative stress can lead to the oxidation of different molecules, causing cell damage ● Free radicals can be generated through various mechanisms, including redox reactions, absorption of extreme energy sources, enzymatic metabolism of exogenous chemicals, and the donation or acceptance of free electrons by transition metals Types of Free Radicals ● Superoxide radicals (O2-): Generated by SOD or oxidases in peroxisomes ● Hydroxyl radicals (OH-): Generated by hydrolysis of water or interaction with metals ● Nitric oxide (NO): Can act as a free radical and can convert to peroxynitrite anion (ONOO) or nitrogen dioxide (NO2) Effects of Free Radicals ● Lipid peroxidation: Destruction of polyunsaturated lipids, leading to membrane damage and increased permeability ● Protein alteration: Fragmented polypeptide chains, leading to protein loss, misfolding, and altered interactions ● DNA damage: Resulting in mutations ● Mitochondrial effects: Damage to ATP generation and compromise in cellular energy Consequences of Mitochondrial Damage ● Mitochondrial permeability transition pore formation: Loss of membrane potential and cell necrosis ● Altered oxidative phosphorylation: ROS formation and damage to cellular components ● Increased permeability of outer membrane: Leakage of proapoptotic proteins and cell death by apoptosis Toxicity and Diseases ● Some drugs and chemicals can generate or be converted to free radicals, leading to toxicity ● Free radicals have been linked to various diseases and disorders Mechanisms to Eliminate Free Radicals ● Spontaneous decay of superoxide into oxygen and hydrogen peroxide Diseases and Disorders Linked to Oxygen-Derived Free Radicals: ● Aging ● Atherosclerosis ● Ischemic brain injury ● Alzheimer disease ● Neurotoxins ● Cancer ● Cardiac myopathy ● Chronic granulomatous disease ● Diabetes mellitus ● Eye disorders (macular degeneration, cataracts) ● Inflammatory disorders ● Iron overload ● Lung disorders (asbestosis, oxygen toxicity, emphysema) ● Nutritional deficiencies ● Radiation injury ● Reperfusion injury ● Rheumatoid arthritis ● Skin disorders ● Toxic states (xenobiotics, metal ions) Methods Contributing to Inactivation or Termination of Free Radicals: ● Antioxidants: Endogenous or exogenous; includes vitamin E, vitamin C, cysteine, glutathione, albumin, ceruloplasmin, transferrin, y-lipoacid, others ● Enzymes: Superoxide dismutase, catalase, glutathione peroxidase Chemical or Toxic Injury: ● Humans are exposed to thousands of chemicals with insufficient toxicologic data ● Chemicals can cause cell stress through oxidative stress, ER stress, heat shock response, DNA damage response, mental stress, inflammation, and osmotic stress ● Xenobiotics are compounds with toxic, mutagenic, or carcinogenic properties ● Many xenobiotics are hepatotoxic (toxic to the liver) ● Chemical compounds used in household cleaning, insect control, etc., can be potential carcinogens and cause liver damage