Done By : Yousef Qandeel & Batool Shafi

Transcription

1 Done By : Yousef Qandeel & Batool Shafi

2 Cytotoxic T lymphocyte has a physiologic role اثناء تطور ال T lymphocyte بكون ف مجموعة منهم بتعادي خال ا الجسم نفسه self( )against و جب التخلص منهم و هنا أت دور cytotoxic T lymphocyte للتخلص من هذه الخال ا عن طر ق physiologic apoptosis

3 Clearance of apoptotic cells Apoptotic cells produce eat me signals Phosphatidyl serine is normally present on the inner leaflet of plasma membrane it becomes on the outer leaflet in apoptotic cell recognized by macrophages Also secreted factors by dying cells induce phagocytosis Some apoptotic bodies express adhesive glycoproteins that are recognized by macrophages Necrosis and apoptosis may coexist DNA damage (seen in apoptosis) activates an enzyme called poly-adp(ribose) polymerase, which depletes cellular supplies of nicotinamide adenine dinucleotide(nad), leading to a fall in ATP levels and ultimately necrosis Even in common situations such as ischemia, it has been suggested that early cell death can be partly attributed to apoptosis, with necrosis supervening later as ischemia worsens Apoptosis induced by some pathologic stimuli may progress to necrosis like some stimuli of DNA damage هون بدنا نعرف انه ف تداخل ب ن necrosis & apoptosis مثال ف حالة تضرر ال DNA هاد مؤشر لبدء عمل ة apoptosis و لكن ف حاالت اذا كان الضرر كب ر ممكن بتحفز ال necrosis بداله او ف حالة ال ischemia اذا تضررت ال DNAاو ال بروت نات ف بتتحفز عمل ة ال apoptosis عن اهم اش نعرف انه مش اذا كان ف عوامل الapoptosis انه عاالك د رح ص ر ممكن ف بعض الحاالت تحول ل necrosis و العكس صح ح Examples of Apoptosis Growth Factor Deprivation: -hormone-sensitive cells deprived of the hormone, -lymphocytes that are not stimulated by antigens and cytokines -neurons deprived of nerve growth factor *In all these situations, apoptosis is triggered by the mitochondrial pathway: -activation of pro-apoptotic members of the Bcl-2 family -decreased synthesis of Bcl-2 and Bcl-xL

4 DNA Damage: When DNA is damaged, the p53(gurdian of the genome) protein arrests the cell cycle (at the G1 phase). Why? if the damage is too great to be repaired successfully, p53 triggers apoptosis (mitochondrial pathway) When p53 is mutated or absent, cells with damaged DNA survive, and in this case What may happen? بص ر ال DNA damage غ ر مس طر عل ه و ا ضا الخل ة ما بتتخلص من هاي الخال ا المصابة بعمل ة apoptosis النه cancer معطل و ما بعمل تحف ز الها و من الممكن ان تفاقم هذا الضرر الى حدوث p53 Accumulation of Misfolded Proteins: -First: unfolded protein response control proper folding) increased synthesis of chaperones in ER (which -Then: if the accumulation is more severe ER stress activates mitochondrial pathway **Cell death by this mechanism is a feature of many neurodegenerative diseases: -Alzheimer -Huntington -Parkinson diseases -..etc

5 chloride channel عبارة عن CFTR التل ف الك س ( بص ر مشاكل ف الرئت ن و البنكر اس Cystic )مرض fibrosis ف اذا كان misfolded ما رح أدي وظ فته و بص ر هاد المرض ( رح ناخد عنه لقدام ) Familial hypercholesterolemia مرض ج ن ؤدي الى تراكم LDL ف الجسم و تصلب الشرا ن المبكر حتى لو كان جسم المصاب بالمرض نح ف Alpha-1-antitrypsin deficiency منع عمل elastase المسؤول عن تدم ر elastic tissue و بما انه الantitrypsin صار misfolded ما رح منع ال elastase بالتال رح شتغل هذا االنز م و دمر ال elastic tissue خاصة ف ال lungs مسببا emphysema و ا ضا تراكم antitrypsin ف ال hepatocyte ER سبب hepatic problem **Autophagy ( self-eating )** = lysosomal digestion of the cell s own components على سب ل المثال ف حاالت ال Atrophy and the cellular degradation ما عنا موارد, بتص ر تستهلك مواردها من جوا و بتهضم ال organelles فالخل ة *Used in times of nutrient deprivation also for clearance of misfolded proteins e.g., when abnormal: neurodegenerative disorders may result من الpathogenesis الل ب حصل ف ها غ ر إنها بتتكون من.. misfolded proteins مشاكل ف ال autophagic system ف ها فما بتقدر تتخلص منهم. بح ث كون عنا misfoldedبتتكون proteins ف نفس الوقت الل ال autophagy مش فعالة ف ه. ال autophagy نفسها ممكن تحفز apoptosis *Autophagy genes (Atg genes) are activated *Organelles + portions of cytosol sequestered within an autophagic vacuole. Autophagic vacuole formed from ribosome-free regions of the ER Vacuole fuses with lysosome autophagolysosome

6 With more severe deprivation autophagy can signal apoptosis Polymorphisms in autophagy genes are associated with inflammatory bowel disease by unknown mechanisms وجدوا عالقة ب ن ال autophagy genes and the inflammatory bowel disease و لكنها غ ر معروفة. "ulcerative المسمى : التهاب القولون التقر ح شمل inflammatory bowel disease "crohn s disease" داء كرون " colitisو معلومة إضاف ة : "هما من أمراض المناعة الذات ة الت هاجم ف ها جهاز المناعة خال ا الجسم نفسها مسببا حدوث التهاب ف النس ج المتأثر. " Now we will discuss 3 topics related to cell injury Intracellular accumulations Extracellular deposition of calcium Aging (of the cells) INTRACELLULAR ACCUMULATIONS Fatty Change (Steatosis) خاصة بال liver Cholesterol and Cholesteryl Esters Proteins Glycogen Pigments: منها ما صنع داخل الخال ا نفسها synthesized in the body مثل ال melanin و منها من خارج الجسم Exogenous مثل ال carbon -Carbon

7 Because of air pollution, if we take sections from the lungs or the lymph nodes draining the lungs, we will find " anthracosis " (macrophages have phagocyted a carbon) على شكل بقع سودة سببها الكربون.. هو مش عامل مرض و لكن اكتشف بالصدفة incidental و ممكن كون زاد عن حده ف أمراض مع نة -Lipofuscin (wear-and-tear pigment) -Melanin الل بتتصنع ف ال melanocytes هدفهم متصوا ال UV light *melanocytes are in the Basal Layar of epidermis و ممكن ال melanin ز د ف خال ا ثان ة مثل ال keratinocytes -Hemosiderin Fatty Change (Steatosis) = accumulation of triglycerides in parenchymal cells Liver is the most common organ. Why? أكثر organ ب عمل metabolism للfat May also occur in heart, skeletal muscle, and others Causes: -toxins زي ما حك نا بال injury ف حالة ال hypoxia مثال ب قل ال ATP وب قل ال oxidation of fatty acids so it accumulates -protein malnutrition as injurious stimulus -diabetes mellitus -obesity Obesity and type2 diabetes:

8 وجود insulin resistance ب كون االنسول ن موجود و لكن الخال ا ما بتستج ب اله فب ص ر some problems in fatty acids metabolism leading to accumulate free fatty acids inside the cells. -anoxia The most common causes of fatty liver disease are: -alcohol NonAlcoholic Fatty Liver Disease (NAFLD) "steatohepatitis" هذا المرض عبارة عن multichange /steatosis المشكلة األساس ة ف ه تراكم ال fat و سببه الرئ س. resistance alcohol then obesity, diabetes and insulin ف خال ا الكبد Alcohol ب نشط انز م dehydrogenase ف الكبد الل ب ز د ال reduced form of NADB و ب ص ر NADBH مما منع ال oxidation of fatty acids فبتتراكم ف الخل ة -DM associated with obesity Cholesterol and Cholesteryl Esters ف diseases معروفة بتراكم ال foamy macrophages(macrophages phagocyting fat,cholesterol and triglycerides) مثل ال atherosclerosis Cholesterol metabolism is important for membrane synthesis Accumulation of lipids (triglycerides, cholesterol, and cholesteryl esters) in phagocytic cells:.different pathologic processes, and atherosclerosis is the most important example. تراكم الكول سترول ف ال tissues بح ث تواجد microphages داخلها كول ست رول تراكمه ف الخال ا الموجودة ف ال intima of the vessels " Called Atheroma تصلب الشرا ن " هذا التراكم سبب injury in intima and blood vessels

9 Proteins Much less common than lipid accumulations Examples: -Kidney: -normally trace amounts of albumin are filtered through the glomerulus and reabsorbed by pinocytosis in the proximal convoluted tubules, but in nephrotic syndrome: بتكون الglomerulus متدمرة فب ص ر albumin ( proteinuria ب طلع بكثرة ف الurine (.. ف مسارها لما تمش ف ال tubules ممكن تتراكم و بتبطل خال ا ال tubules تلحق تعمللها absorption فبالتال ب تراكم البروت ن على شكل eosinophilic droplets Heavy proteinuria reabsorption of protein vesicles accumulate on H&E: pink, hyaline cytoplasmic droplets the process is reversible Other examples of protein accumulation Immunoglobulins in the RER of some plasma cells لما ال plasma cells تتنشط ف بعض األمراض ز ادة بتفرز Immunoglobulins كث ر فممكن تراكم بال RER و بتعمل تكتالت bodies" "eosinophilic اسمهم Russell bodies rounded, eosinophilic bodies called:russell bodies Alcoholic hyaline in the liver Hyaline bodies and it's also eosinophilic bodies Neurofibrillary tangles in neurons In alzheimer disease accumulation of misfolded proteins which appear under LM as Neurofibrillary tangles like this :

10 ف حاالت ال diabetes االنسول ن ب ش ل الغلوكوز من الدم فلما ما شتغل بتص ر كم ة الغلوكوز بالدم كب رة فبتز د كم ة الغال كوج ن ف ال. hepatocytes Glycogen بتسبب تراكم للغال كوج ن. Abnormalities in the metabolism of either glucose or glycogen Insulin problems Examples: -DM: glycogen accumulates in: -renal tubular epithelium -cardiac myocytes -β cells of the islets of Langerhans -Glycogen storage diseases (glycogenoses) و ممكن الغال كوج ن تراكم ف امراض مع نة اسمها glycogen storage diseases اذا ما ف انز مات مع نة تحطم الغال كوج ن ممكن تراكم ف خال ا... "ف المحاضرة الماض ة تم طرح ال RBCs كمثال على ال apoptosis و لكن هذا ال مكن فه ال تحتوي على nucleus و ه وقت تدم رها بتروح عال spleen و بتنبلع بال. macrophages erythrocyte precursors in bone marrow that make RBCs might have through apoptosis mechanisms " Pigments

11 Exogenous or synthesized in the body Carbon (an example is coal dust + air pollution) anthracosis the most common exogenous pigment Lipofuscin, or wear-and-tear pigment in heart, liver and brain due to aging or atrophy = complexes of lipid and protein that derive from the free radical catalyzed peroxidation of polyunsaturated lipids of subcellular membranes *not injurious, but marker of previous free radical injury *What is brown atrophy? *perinuclear electron-dense granules on EM but it's brown pigments on LM تجمع لنواتج ال damage ف ال membranes مع proteins هسا ال membranes بال free radicals injury لما كانت تدمر ال membrane كانت تعمل lipid peroxidation.. تحطم الphospholipids membrane و ب نتج عن ذلك peroxides فب ز د تراكم الLipofuscin ) brown under LM( و ه عبارة عن proteins و peroxides هسا هاي تدل على ال injury مش بتسببه ال aging من مسببات ز ادة أداءال free radicals فهو ز د ترك زال ROS مما ز د من تدم رال membrane و بالتال ز ادة ال lipoflucin Melanin: can also be accumulated in: -keratinocytes -macrophages Hemosiderin: hemoglobin-derived granular pigment برضو صبغة ثان ة هو عبارة عن iron جوا بروت ن عن خزنه ف الtissue اسم البروت ن ferritin بروت ن apoferritin ب رتبط مع ال iron ب ص ر اسمهferritin عن الشكل التخز ن لل iron ف الجسم داخل ال ferritin و الخال ا هو tissues

12 الHemosiderin هو تراكم هذا الferritin على بعضه local or systemic excess of iron (most of the time pathological) in cells, iron + apoferritin = ferritin micelles (stored as this) hemosiderin = large aggregates of ferritin micelles appears on LM (golden yellow to brown) special stain for iron: Prussian blue small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded btw : Hemosiderin is a product of HB degradation Excessive deposition of hemosiderin = hemosiderosis hereditary disease with this is called: hereditary hemochromatosis. سببه ز ادة امتصاص ال iron من ال GI باق المواض ع بالسال دات الباق ة الدكتور فضل التعق ب عل ها خالل الالبات *