Cell Adaptation & Injury PDF

Lec.1 Dr.Sura Akram CELL ADDAPTATION & INJURY 🔹 Homeostasis: The ability of the cell to maintain a dynamically stable state, in which the cells are continuously adjusting their structure and function, within a narrow...

Lec.1 Dr.Sura Akram CELL ADDAPTATION & INJURY 🔹 Homeostasis: The ability of the cell to maintain a dynamically stable state, in which the cells are continuously adjusting their structure and function, within a narrow range, to deal with the continually changing extra-cellular environments. ❖ Adaptations: modification of the homeostatic state of the cells and achieve a new steady state to counteract severe external changes (physiological or pathological), to avoid cell injury & death. ❖ The morphological & functional changes induced by the injury may be reversible, i.e. the cells return to a normal state on the removal of the offending agent, or irreversible, Irreversible changes ultimately eventuate in cell death. CELLULAR ADAPTATIONS Adaptations are reversible changes divided into physiologic & pathologic. 1-Hypertrophy: -An increase in the size of cells (Increase structural proteins) that results in enlargement of the organ. Occur in cells that have limited capacity to divide. Causes of hypertrophy include: (1) Increased functional demand. (2) Growth factors. (3) Hormonal stimulation. Hypertrophy can be physiological: -Skeletal muscles in athletes or physiologic enlargement of the uterus during pregnancy due to estrogen-stimulated smooth muscle. Pathologic: cardiomegaly secondary due to hypertension or aortic valve disease. 2-Hyperplasia: An increase in the number of cells. It takes place only if the cells are capable of replication(mitosis) (therefore, not muscle or nerve cell). Can be Physiological: -Hormonal hyperplasia: like the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy. The enlargement of the gravid uterus is due to combination of hypertrophy & hyperplasia. -Compensatory hyperplasia:occurs when aportion of the of the tissue is removed or diseased. For example, when a liver is partially resected, mitotic activity in the remaining cells begins restore the liver to its normal state. Pathological: Mostly caused by excessive hormonal or growth factor stimulation. Endometrial hyperplasia: this results from persistent or excessive estrogen stimulation of the endometrium (common cause of abnormal uterine bleeding). Benign prostatic hyperplasia due to hormonal stimulation by androgens. 3-Atrophy:-refers to shrinkage in the size of the cell due to loss of its constituent substances (a combination of decreased protein synthesis and increased protein degradation). Causes of atrophy include: 1-Decrease workload e.g. muscular atrophy due to immobilization in fracture limb. 2-Denervation (loss of nerve supply) as in paralysis. 3-Ischemia (decrease of blood supply) as in aging. 4-Malnutrition as in starvation 5-Loss of endocrine stimulation e.g atrophy of uterus after menopause.  4. Metaplasia: -The conversion of one cell type to another cell type that might have a better chance of survival under certain circumstances. -Metaplasia usually occurs in response to chronic irritation or inflammation. -It is a genetic “reprogramming” of stem cells and not changing of differentiated cells. ❖ examples for metaplasia include: 🔹Cigarettes smokers: normal ciliated columnar epithelial cells of the trachea and bronchi often are replaced by stratified squamous epithelial cells. 🔹Vitamin A deficiency: can induce squamous metaplasia. 🔹Chronic gastric reflux: normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium. -The influences that induce metaplastic change in an epithelium, if persistent, may predispose to malignant transformation.  Cell injury Occur When there is no enough time for adaptive responses to take place as in sever injurious agent. Causes of Cell Injury 1-Hypoxia and ischemia: Insufficient supply of oxygen interferes with aerobic oxidative respiration and is a common cause of cell injury and death. Causes of hypoxia: 🔹 Reduced blood flow (Ischemia). 🔹Inadequate oxygenation of the blood due to cardio-respiratory failure ( e.g pneumonia ). 🔹Reduction in the oxygen-carrying capacity of the blood, as in anemia or carbon monoxide (CO) poisoning. 2-Physical Agents: trauma, extremes of temperatures, radiation, electric shock. 3-Chemical Agents: include concentrated glucose or salt(hypertonic concentration). Poisons (cyanide), alcohol, as well as drugs. 4-Infectious agents: bacteria, viruses, fungi and parasites. 5-Immunological: hypersensitivity reactions and autoimmune diseases. 6-Genetic defects: genetic abnormalities as an extra chromosome, as in Down syndrome. 7-Nutritional Imbalances: Protein-calorie deficiencies, Deficiencies of vitamins,Excess of cholesterol predisposes to atherosclerosis; obesity is associated with several important diseases, such as diabetes and cancer. MECHANISMS OF CELL INJURY The outcomes of the interaction between injurious agents and cells depend on: -The injurious agent: its type, severity, and the duration of its application to the cells. -The cells exposed to the injury: its type,status and their genetic makeup. -the underlying mechanisms of cellular injury usually fall into one of two categories: 1.Hypoxic injury 2. Free radical injury 1-Hypoxic cell injury -Hypoxia (ATP depletion) is a lack of oxygen in cells and tissues that generally results from ischemia. -During periods of hypoxia, aerobic metabolism of the cells begins to fail this leads to dramatic decreases in energy production (ATP) within the cells. -Hypoxic cells begin to swell as energy-driven processes (such as ATP-driven ion pumps). The pH of the cellular environment begins to decrease as waste products (such as lactic acid, a product of anaerobic metabolism) begin to accumulate. -The cellular injury process may be reversible, if oxygen is quickly restored, or irreversible and lead to cell death. Certain tissues such as the brain are particularly sensitive to hypoxic injury. Death of brain tissues can occur only 4 to 6 minutes after hypoxia begins.  Mechanism of hypoxic cellular injury: Hypoxia and toxic chemicals (e.g. cyanide which inhibits cytochrome oxidase blocking oxidative phosphorylation) are the main causes for ATP depletion. Depletion of ATP produces the followings: A. Reduction of the activity of energy dependent plasma membrane sodium pump. This causes Na+ to be restricted inside the cell and K+ outside. An increased intracellular Na+ results in water retention that leads to cell edema. B. Switch to anaerobic glycolysis. If ATP depletion due to hypoxia, this will block oxidative phosphorylation for ATP production and cells undergo anaerobic glycolysis to maintain energy and ATP production. This anaerobic glycolysis will produce lactic acid that decreases intracellular PH (acidic cytoplasm) which interferes with the optimal activity of many cellular enzymes. C.Increased in intracellular Ca+: failure of Ca+pump leads to influx of Ca+ that have damaging effect on many cellular components. D.Structural disruption of the protein synthesis apparatus. With prolong ATP depletion there will be reduction in protein synthesis due to detachment of ribosomes from rough endoplasmic reticulum (rough ER).  2-Free radical injury Oxygen-derived free radicals (OFR) are produced as a by product of mitochondrial respiration. These are chemically reactive, having single unpaired electron in the outer orbit. OFR include: o2- (superoxide), H2O2 (hydrogen peroxide), OH- (hydroxyl radicle) and 1 O (singlet oxygen). OFR can damage lipids, proteins and nucleic acids leading to various forms of cell injury. Cells normally have defense against OFR by antioxidant materials like glutathione, vit C and others. An imbalance between generation of OFR and level of antioxidant materials in the body called oxidative stress. Free radicals can injure the cells by the following mechanisms. 1-Lipid Peroxidation. Free radicals attack the double bonds of polyunsaturated lipid in the membrane. 2-DNA Fragmentation. Free radicals attack the Thymine base in the DNA of nucleus which result in Single Strand Breaks. 3-Gross – Linkage of Proteins.Free radicals promote sulfhydryl mediated proteins cross linkage (SH- SH) which result in degradation & loss of enzymatic activities.  Cell death There are two modes of cell death: A. Necrosis: cell death due to degrading action of enzymes on irreversibly damaged cells with denaturation of cellular proteins. cellular swelling and presence of inflammation are characteristic features. It includes morphological features: cytoplasmic as well as nuclear changes. 1- Cytoplasmic changes: in hematoxylin-eosin stain (H&E stain), hematoxylin (basic dye) stains the acidic cell materials (nucleus) blue whereas eosin (acidic dye) stains alkaline cell materials (cytoplasm) pink. Necrotic cells cytoplasm becomes more alkaline and stains deeply with eosin (eosinophilic) than viable cells because: Loss of cytoplasmic RNA (RNA acidic material) and increase binding of eosin to denatured protein. Nuclear changes: include chromatin aggregation which is the earliest nuclear changes, after that nucleus 1-Pyknosis: nuclear shrinkage. 2-karyorrhexis: fragmentation of the nucleus 3-karyolysis: disappearance of nucleus  Types of cell Necrosis: A/Coagulation necrosis: Tissue structure is preserved for several days. Result from sever ischemia Occur in all solid organs such as heart, kidney except the brain. B/Liquefactive necrosis: Characterized by complete digestion of dead cells by enzymes. resulting in transformation of the affected tissue into a liquid viscous mass enclosed within a cystic cavity. It was seen in two situations: 1. Brain infarct: ischemic destruction of brain tissue. 2. Abscess that occurs after bacterial and fungal infection. C/Caseous necrosis: Have the combined features of both Coagulative and liquefactive necrosis seen in the center of TB (tuberculous infection) granuloma. The term "caseous" (cheese-like) is derived from the yellow- white appearance of the area of necrosis D/Fat necrosis: specific pattern of cell death seen in adipose tissue due to action of lipase enzyme as in acute pancreatitis. Also, can be seen after trauma of fatty tissuee.g. trauma of female breast. E/Gangrenous necrosis: it is representing combination of coagulative necrosis (ischemia) of tissue followed by liquefactive necrosis by liquefactive action of enzymes derived from bacteria and inflammatory cells. Gangrene is classified into 3 types 1. Dry gangrene 2. Wet gangrene 3. Gas gangrene  A. Dry Gangrene occurs in the distal part of the limb due to ischemia, Typical examples of a dry gangrene are on the toes and feet of an old patient due to Atherosclerosis. Usually initiated at the toe region which is farthest from the bloody region, slowly grows upwards and reaches a point where the blood supply is adequate enough to keep the whole tissue viable. The affected part is dry, shrunken and dark black. The dark coloration is due to liberation of hemoglobin from hemolyzed red blood cells which is converted by hydrogen sulfide (H2S) produced by the bacteria, resulting in formation of black iron sulfide that remains in the tissues A “Line of separation” is well formed between the gangrenous part and the viable part. B. Wet gangrene: Usually occurs in the moist tissues and organs such as the Mouth, Bowel, Lung, Cervix, and Vulva. Diabetic leg & Bedsores are other examples with high sugar contents in the necrosis tissue which is favorable for the bacteria to grow. Wet gangrene usually develops rapidly due to blockage of venous and less commonly arterial blood flow from thrombosis or embolism. There is no clear demarcation of any line of separation. C-Gas gangrene: -Is a special form of wet gangrene that is caused in muscle can also occur as a complication of operation on colon which usually contains the bacteria Clostridia. Clostridia(Clostridium perfringens) which is a gram positive anaerobic bacteria) which enters into the tissues through open contaminated wounds  B-Apoptosis: Distinct pattern of cell death differs from necrosis in that it is an internally controlled energy - dependent process for deletion of un wanted cells without damage to the tissue that containing them (without inflammation). cells undergo apoptosis showing cytoplasmic membrane blebs and cells fragmented to apoptotic bodies engulfed by phagocytosis. Apoptosis can occur in: 1-During embryogenesis for organmorphogenesis and remodeling. 2-Hormone dependent involution eg shedding of endometrium during menstrual cycle. 3-Physiological Deletion of aged cells of blood, skin, intestinal epithelia 4-Deletion of inappropriately proliferated cells e.g tumor cell