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Pathophysiology /inflammation Done by :Marwa Al-gharabat L05 : In last lecture we talked about systemic effect of inflammation , and we talked about “fever “.but note that fever and inflammation are not correlate with each other ,it can be drug induced . Now : what is the different between fever and hyperthermia ?? The worst one is the hyperthermia , Fever →↑in body temp. mediated or (controlled) by hypothalamus ,in response to inflammatory mediator like PGE2 or pyrogen by (1-4)c⁰, pyrogen is any thing that cause elevation in body temp. . Hyperthermia →↑in body temp. due to imbalance between heat production and cooling system in the body. So hyperthermia can result from ↓ in cooling system in the body e.x: sweating , there are some drugs that ↓ sweating such as (anti-muscarinic drug ) by inhibition of M3 receptor to prevent sweating →↑ in body temp. When someone exposure to the sun , his body temp. will elevate ,but this increase is not controlled by CNS or the body system so it can be elevated till death 0_0 ! so hyper and hypothermia is a serious condition because they are not controlled,if it’s not too late we have to get back the balance . All the systemic effect of the inflammation are non-specific sign of inflammation , they can be indicate the inflammation but can’t determine the type and cause of it, if we have a fever that not necessary to mean that we have an inflammation . For example in leukocytosis “↑ in WBCs no. “ not always due to infection or inflammation , if it elevated we look at other sign,and we look if we have many sign that indicate an inflammation 1 **Cellular responses to stress and toxic substances :(not systemic) •Cells have specific function and morphology •Nevertheless, they are able to handle physiologic demands, maintaining a steady state called homeostasis •Adaptations are reversible functional and structural responses to more severe physiologic stresses and some pathologic stimuli -e.x : if blood glucose ↑ , ᵦ cell in pancreas will ↑ the release and synthesis of insulin this is adaptation and it’s reversible -Homeostasis → normal response ,to express balance •Cell injury (reversible) follows if the limits of adaptive responses are exceeded or if cells are exposed to injurious agents or stress : -If the stress exceed the cell ability to adapt ,or when the magnitude of the stress or the rate of the exposure to the stress are exceed the cell ability to adapt , to certain point this injury is reversible due to repair system in the cell . The worst type of injury in the cell is injury of the DNA because this will change the genetic material of the cell tissue , this type is highly controlled due to repair system *If the injury is too extensive and the repair system had been failed to fix the injury → apoptosis “ programmed cell death “ it’s always better to get rid of the severely damaged cell than the risk of formation of cancer cell , it’s one of the key strategy of cancer management In non-phase drug such as (alkalating drug)cause →extensive damage of the cell→ formation of cancer cell due to ↑ proliferation of the cell (extensive damage → cell under go apoptosis ) Apoptosis process require an energy ATP : no ATP →no apoptosis and the injury converted to necrosis which is trigger of inflammation →more damaging to the surrounding tissue . 2 •Irreversible cell injury and ultimately cell death (necrosis/apoptosis) occurs if the stimulus persists or is severe enough from the beginning or if the rate\magnitude of exposure to the stress is higher than the cell ability to adapt •Metabolic derangements in cells and chronic injury may be associated with intracellular accumulations of a number of substances, including proteins, lipids, and carbohydrates E.x: Alzheimer disease ,due to unknown reason , and it’s treatment is to slow it not to cure , in general it’s occur due to degradation cholinergic neurons due to accumulation of protein . **REMEMBER : simple cell injury →reversible injury . Sever and extensive injury → irreversible injury →cell death . •Calcium is often deposited at sites of cell death, resulting in pathologic calcification One of the method to test the ischemic damage in ischemic heart disease is to measure the deposited Ca in the coronary artery , if Ca is ↑ so more necrosis tissue are coming on 0_0 •Cell aging is accompanied by characteristic morphologic and functional changes e.x: RBCs life spam is 120 day , after that it will undergo degradation in the spleen (aging ), aging is not apoptosis or necrosis ,it’s a physiological response to the end of life spam .” renew of the cell “. NOTE : Magnitutede OR high rate of injury → necrosis OR apoptosis ↓ ↓ No ATP There is ATP 3 Go back to the table in slide 45 for more example “ it’s included” *Adaptations of cellular growth and differentiation 1.Hypertrophy: an increase in the size of cells, resulting in an increase in the size of the organ, but hyperplasia is an ↑the no. of the cells Hyperplasia: is an increase in the number of cells in an organ or tissue, usually resulting in increased mass of the organ or tissue (physiologic or pathologic). We can use both term interchangeably , for example : BPH benign prostatic hyperplasia and some text book use hypertrophy . 4 •Non-dividing cells (e.g., myocardial fibers) increased tissue mass is due to hypertrophy. These cell likely to undergo hypertrophy ,so we say left ventricle hypertrophy → due to ↑ in cells size not the no. . •Hypertrophy can be physiologic or pathologic and is caused by increased functional demand or by stimulation by hormones and growth factors e.x:- physiologic : hypertrophy in heart due to ↑ in blood pressure so one way to adapt is to ↑ size of the cells → more strength in bumping the blood to limited point then collapse occur → significant ↓ in strength , e.x : in rubber band . -hormonal factor : development in organ such as in female chest . Metaplasia: is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. \ the transformation of one type of cells to another type of cells . e.x: in gastroesophagial reflex disease due to exposure of the esophagus to acids and by time →change in the type of the cells in lower part and become like cells in stomach , metaplasia can convert into cancer . -displasia , anaplasia and distrophy : Displsia → poorly differentiation of cells ( dysplastic tissue ) Anaplasia → completely loss of differentiation . Distrophy →literally it’s mean ↑ or ↓ in cells size ( abnormal size ) Atrophy: is reduced size of an organ or tissue resulting from a decrease in cell size and number (physiologic or pathologic). 5 Physiologic hyperplasia can be divided into: (1) hormonal hyperplasia, which increases the functional capacity of a tissue when needed, and (2) compensatory hyperplasia, which increases tissue mass after damage or partial resection → if we remove part of the liver the physiological response that hepatic cell will proliferate to regenerate the missing part (( such as liver transplantation )).note that hyperplasia have certain doubling time before they age and die , limited copies, doubling, and division time and that depending on telomeres . Mechanisms of hyperplasia: - It occurs due to growth factor–driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells Mature cell → differentiate to one type of cells. Stem cell → differentiate to any type of cells . Common causes of atrophy are the following: - Decreased workload (atrophy of disuse) *E.x: in muscle - Loss of innervation (denervation atrophy) *Some proper function need to be controlled by ANS - Diminished blood supply *which lead to →↓oxygen →↓in size of the cell and some time lead to necrosis - Inadequate nutrition *in malnutrition condition which lead to ↓ in muscle mass - Loss of endocrine stimulation *↓in hormone secretion , certain glands are controlled by other hormone to give a secretion , when these hormones are absente →atrophy in the gland . - Pressure *like over using of the tissue 6 The most common epithelial metaplasia is columnar to squamous as occurs in the respiratory tract in response to chronic irritation Like COPD patient . CACHEXIA : It’s basically muscle wasting or degeneration of atrophy of muscle due to excessive inflammation which can lead to tissue atrophy especially in the muscle , and this condition called cachexia , so too much exposure to TNF ( tumor necrosis factor (inflammatory mediator )) will trigger shrinkage of the cell → cell death .. “ excessive inflammation → cell atrophy “ •Mechanism of metaplasia: - Occurs as a result of reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue. The site with ↑ turn over of the cell like esophagus and respiratory tract, if the mucosa is in direct exposure to an irritant →↑ turnover of the cell , then the cell convert to the same tupe of the cell . BUT , if we have continous irritation → that’s lead to reprogramming of the cell and when the cells that in direct exposure to the irritant die , the undifferentiated cell will differentiate to different type of cells in response to stimuli .. -the dangerous thing about metaplasia that it can lead to transformation of neoplastic cell . *Typically : the phases that the cells undergo before transformation into neoplastic cells , Normal cells → metaplasia → dysplasia →neoplastic cell “carcinoma in situ “ →↑ in size of the cells , in situ mean that we can’t see it by naked eye , but by histological examination ,cell will be different 7 APOPTOSIS : \ Causes of apoptosis: - occurs normally both during development ( during development of the fetus , some cells are presented and then it’s disappear) and throughout adulthood e.x:in fetus there is a channel between aorta and ventricles “patent ductus arteriosus “ , and this shunt help to reduce the pressure in the ventricles , after delivery this channel closed ( during pregnancy it’s maintain by progesterone , after delivery this shunt closed by apoptosis . - serves to eliminate unwanted, aged or potentially harmful cells (physiologic situations)to prevent the risk of neoplastic formation from occur . - in certain instances, diseased cells become damaged beyond repair and are eliminated (pathologic situations) The cell must have enough ATP in order to go through apoptosis . The steps : The nucleus affected in the first step , them the membrane blebbing due to morphologic changes , Apoptotic body “ not functional remnant of the original cell “would be an evidence of apoptosis and we use these bodies to indicate the degree of apoptosis by morphological examination , because there a certain enzyme that activated in the apoptosis , depending on it’s activity we can determine the activity of the apoptosis . Look at figure on slide 58 : Autophagy is athird type of cells death actually it’s subset of apoptosis the difference is the sequence of morphologic change , in autophagy vacuoles is formed inside the cells which contain a lysozyme to lyse protein an internal content of the cells . 8 Both apoptosis and autophagy give apoptotic bodies . What happen in necrosis :dumping of the intracellular content in the surrounding tissue and this content is a pro-inflammatory mediator. It’s not easy to trigger the apoptosis , it’s very controlled , irreversible ,unidirectional, if the cells undergo the apoptosis ther is no chance to repair . Apoptotic body prevent the cell content from release to the surrounding tissue . Apoptosis in Physiologic Situations •Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissues. 9 •It is important in the following physiologic situations: -The programmed destruction of cells during embryogenesis. -Involution of hormone-dependent tissues upon hormone withdrawal. -Cell loss in proliferating cell populations. -Elimination of potentially harmful self-reactive lymphocytes. - Death of host cells that have served their useful purpose Apoptosis in Pathologic Conditions •Apoptosis eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage. •Death by apoptosis is responsible for loss of cells in a variety of pathologic states: -DNA damage. -Accumulation of misfolded proteins. -Cell death in certain infections. -Pathologic atrophy in parenchymal organs after duct obstruction. MORPHOLOGIC AND BIOCHEMICAL CHANGES IN APOPTOSIS •Morphologic changes: - Cell shrinkage - Chromatin condensation - Formation of cytoplasmic blebs and apoptotic bodies - Phagocytosis of apoptotic cells or cell bodies, usually by macrophages Biochemical Features of Apoptosis •Activation of Caspases •DNA and Protein Breakdown •Membrane Alterations and Recognition by Phagocytes 10 Initiation of apoptosis occurs principally by signals from two distinct pathways: - the intrinsic (mitochondrial) pathway “ the common pathway” - the extrinsic (death receptor–initiated) pathway Good luck 11