Cell Injury Apoptosis.
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Transcript of Cell Injury Apoptosis.
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PATHOLOGYPathology is literally the study (logos) of
suffering (pathos)
Traditionally divided into general & special / systemic pathology
Four aspects: etiology pathogenesis morphologic changes functional
derangement and clinical significance
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Cellular responses to injuryAcute cell injury• Reversible cell injury• Irreversible cell injury (cell death)
Necrosis Apoptosis
Subcellular alterations in persistent sublethal and chronic injury
• Cellular adaptations• Intracellular accumulation• Cell aging
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Pengertian dasar dalam jejas sel• Jawaban sel terhadap stimuli/jejas tergantung pada jenis jejas,
lamanya, dan beratnya• Akibat jejas tergantung pada jenis sel, keadaan/status sel
(nutrisional, hormonal, dll), serta daya adaptasi (otot lurik tahan 2-3 jam, otot jantung hanya tahan 20-30 menit)
• Ada 4 sistem intraselular yang rentan:1. Keutuhan membran sel homeostasis ionik dan osmotik2. Respirasi aerobik penting dalam produksi energi ATP3. Sintesis protein4. Keutuhan aparatus genetik
• Elemen struktural dan biokimiawi sangat erat• Perubahan morfologik terjadi sesudah perubahan kimiawi
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The relationships between normal, adapted, reversible injured, and dead cells
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ETIOLOGY OF CELL INJURY• Oxygen deprivation
• Physical agents• Chemical agents• Infectious agents
• Immunologic reactions• Genetic derangements• Nutrition imbalances
• Aging
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Mekanisme Jejas SelFakta• Banyak penyebab jejas sel, tetapi tidak
semuanya fatal• Banyak makromolekul, enzim, dan organela
dalam sel yang saling tergantung sulit menentukan target pertama jejas
• “Point of no return” pada dasarnya masih sulit ditentukan letaknya (”cut-off point” yang tepat?)
• Tidak ada satu jalur final ke kematian sel yang umum.
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Schematic representation of a normal, reversible, and
irreversible injury(ultrastructural changes)
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Sequence of events in ischemic injury
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The consequences of increased cytosolic calcium
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Mechanism of membrane damage in ischemia and reperfusion
REPERFUSION
Loss of intracellular amino acids
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Jejas KimiawiAda 2 bentuk mekanisme umum:• Bahan yang aktif biologik
Menyatu dengan komponen molekular kritikal dari organela: merkuri + kelompok sulfhidril membran sel / protein lain Inhibisi transport tergantung ATP & peningkatan permeabilitas membran. Contoh lain: obat sitotoksik & antibiotik
• Bahan yang tidak aktif biologik tetapi harus berkonversi menjadi metabolit toksik reaktif Contoh: CCl4 CCl3
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CCl4 toxicity: cellular events fatty change
and necrosis
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RADIKAL BEBASDefinisi: senyawa kimia yang mempunyai elektron tunggal di
orbit terluar.Sifat:• sangat reaktif dan tidak stabil siap bereaksi dengan apa
saja baik anorganik maupun organik (protein, lemak, karbohidrat)
• inisiasi reaksi otokatalitik• Dapat diinisiasi di dalam sel dengan:
- Energi radiasi- Endogen: reaksi reduksi-oksidasi pada metabolisme normal- Eksogen: metabolisma enzimatik obat/racun: CCl4 CCl3
Radikal bebas yang biologik penting:• Oksigen :superoksida (O2
o), hidrogen peroksida (H2O2), ion hidroksil (OHo)
• Karbon: CCl3o
• Nitrogen : nitrik oksida (NOo)
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The Role of O2 in Cell Injury
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Free radical induced cell injury
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Bentuk jejas oleh radikal bebas1. Peroksidasi lipid pada membran sel ikatan
ganda pada lemak polyunsturated membran sel reaksi berantai otokatalitik
2. Lesi pada DNA: radikal bebas bereaksi dengan DNA nuklear dan mitokondrial pecahan DNA single-strand nekrosis sel atau keganasan
3. Cross-linking protein (dimediasi oleh sulfhydril) degradasi atau hilangnya aktivitas enzimatik.
4. Fragmentasi polipeptida
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Jejas ReversibelDengan mikroskop cahaya tampak sebagai• Cellular swelling
Perubahan awal jejas sel akibat dari kegagalan pemeliharaan homeostatsis ionik dan cairan vakuolisasi halus karena patahnya RE sel bengkak, pucat, turgor meningkat hydropic change (vacuolar degeneration)
• Fatty changeAkibat dari jejas hipoksik dan berbagai bentuk jejas toksik dan metabolik vakuola lemak & infiltrasi lemak
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Hydropic Change
Swollen cell with clear cytoplasm (hydropic degeneration)
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Perubahan sub-selular jejas sel
1. Hipertrofi retikulum endoplasma halus (SER)Akibat dari pemakaian barbiturat jangka panjang
2. Perubahan mitokondrialDapat berupa pembengkakan, peningkatan/penurunan jumlah
3. Abnormalitas sitoskeleton (mikrotubuli: Ø 20-25nm, filamen aktin tipis: Ø 6-8nm, filamen miosin tebal: Ø 10nm)- fungsi sel menurun: lokomosi & gerakan organela- akumulasi material fibrilar
4. Lisosom- otolisis & heterolisis
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Autophagy vs
Heterophagy
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Nekrosis• Perubahan morfologik akibat jejas letal, berupa degradasi
progresif karena kerja enzim-enzim• Morfologi:
- Inti: piknosis, kariolisis, karioreksis- eosinofilia meningkat: karena meningkatnya daya ikat cat eosin, dan hilangnya bagian basofil- Tampak lebih jernih: karena hilangnya partikel glikogen - Vakuolisasi sitoplasma: digesti enzimatik pada organela lapuk- Kalsifikasi: terutama berasal dari Ca++ ekstraselular
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Jenis Nekrosis• Nekrosis koagulatif gangren kering
- akibat keasaman intraselular denaturasi protein struktural dan enzim
• Nekrosis liquefaktif gangren basah- akibat digesti sel oleh enzim otolisis & heterolisis
• Bentuk kusus:- Nekrosis fibrinoid (timbunan fibrin, imunoglobulin, dan protein plasma yang lain)- Nekrosis lemak (enzymatic & traumatic fat necrosis)- Nekrosis kaseosa
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Coagulation necrosis
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Coagulative & lequefactive necrosis
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Caseous necrosis
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Fatty Necrosis saponification
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Perubahan ultrastruktur1. Perubahan membran plama: bleb
(melepuh), rusaknya mikrovili, dan perlekatan interselular longgar
2. Perubahan mitokondria: membengkak dan penebalan amorf kaya lemak
3. Dilatasi retikulum endoplasmik ribosom lepas dan distorsi polisom
4. Perubahan inti, dengan disagregasi elemen granular dan fibrilar
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Electron micrograph of normal, reversible,
and irreversible
injury of epithelial
cells
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Heat-shock protein• Jenis protein yang normal ada dalam sel
dapat menahan jejas yang dapat menimbulkan cedera
• Ada 3 keluarga: Hsp70, Hsp60, & Hsp90• Jejas yang meningkatkan ekspresi Hsp:
- jejas iskemik : kardial & neuronal- jejas reperfusi : jantung kelinci- jejas toksik : adriamisin
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ADAPTASI SEL
HIPERPLASIHIPERTROFI
ATROFIMETAPLASI
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HIPERPLASIA• Pertambahan jumlah sel dalam organ atau jaringan• Hiperplasia dapat fisiologik atau patologik• Fisiologik:
– Hiperplasia hormonal menarche kehamilan menyusui– Hiperplasia kompensatorik (reseksi hati)
• Sebagian besar hiperplasia patologik disebabkan karena stimulasi oleh hormon yang berlebihan atau GF. Bisa juga karena infeksi virus
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Kapasitas proliferatif sel
(hipotesis telomer-
telomerase)
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Hiperplasi Kompensatorik
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Hipeplasia of liver cells post partial hepatectomy
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Hipertrofi
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ATROFI
Brain in 82 year old male 36 year old male
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METAPLASIA• Perubahan reversibel dari sel dewasa
tertentu menjadi sel dewasa bentuk lain• Sel kolumnar squamous complex• Squamous complex kolumnar• Sel jaringan ikat jaringan tulang
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Barret’s metaplasia
METAPLASIA
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Lintas diferensiasi stem cell
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Intracellular accumulation
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Fatty Change (liver)
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Fatty Liver
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Fatty Change (cholesterolosis)
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Lipofuchsin pigment in cardiac myocyte
Perinuclear and intra-lysosomal
location
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Hemosiderin granules in liver cells
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Model Kalsifikasi
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Kalsifikasi:-kalsifikasi distrofik-kalsifikasi metastatik
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Aging Process
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Proses Penuaan
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Cellular senescent is multifactorial involves the commutative effects of both:
• Intrinsic molecular clock of cellular aging• Extrinsic stressors of the cellular environment
(wear & tear theory)
Aging Process
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Intrinsic Cellular AgingHuman fibroblasts in culture have
finite life span:• Adult human fibroblast in culture stop dividing
and become senescent after about 50 doublings Hayflick phenomenon
• Fibroblast from neonates go through about 65 doublings before they cease dividing
• Progeria patient: only 35 doublings
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Aktivitas Telomerase
Short, multiply repeated sequenc of
nontranscribed DNA (TTAGGG)
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Diseases of Premature Aging
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Progeria
A 10-year old girl shows the typical features of premature aging associated with progeria
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ApoptosisKematian / hilangnya sel-sel tunggal yang tersebar di
antara sel sehat, merupakan suatu bentuk kematian yang telah didisain
untuk mengeliminasi sel-sel yang tidak dikehendaki,
melalui seri aktivitas peristiwa oleh satu set produk gena yang bertanggungjawab,
yang terkoordinasi dan terprogram secara internal
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Peran apoptosis1. Dalam masa tumbuh kembang2. Mekanisma homeostatik untuk
memelihara populasi sel dalam jaringan3. Mekanisma pertahanan pada reaksi imun4. Pada saat sel diserang penyakit atau
bahan berbahaya5. Pada proses penuaan
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Apoptosis in Physiologic Stuations• The programmed destruction of cells during embryogenesis• Hormone dependent involution in the adults endometrial
cells breakdown during menstrual cycle, ovarian follicular atresia in menopause, regressing lactating breast after weaning, prostatic atrophy after castration
• Cell deletion in proliferating cell populations intestinal crypt epithelia, in order to maintain constant number
• Death of host cells that have served their useful purpose neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response
• Elimination of potentially harmful self-reactive lymphocytes before or after completed maturation
• Cell death induced by cytotoxic T cells defense mechanism against viruses and tumors, and cellular rejection of transplan
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Apoptosis in Pathologic Condition
• Cell death produced by a variety of injurious stimuli radiation therapy and chemotherapy
• Cell injury in certain viral diseases viral hepatitis, loss of infected cells is largely because of apoptosis
• Pathologic atrophy in parenchymal organs after duct obstruction pancreas, parotid gland, kidney
• Cell death in tumors most frequently during regression
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MORFOLOGI Sekwen perubahan ultrastruktural
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Apoptosis pada kulit dengan reaksi imun
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Gambaran BiokimiawiProtein Cleavage• Hidrolisis yang melibatkan beberpa anggota proteinase sistein
(caspase juga memicu aktivitas endonuklease)Protein cross-linking• Transglutaminase: protein sitoplasmik jisim-jisim apoptotikPecahnya DNA• DNA pecah 50 – 300 kbp• Pemecahan internukleosomal oleh endonuklease (tergantung
Ca++ dan Mg++) endonukleosom (120 – 200 kbp) DNA ladders
Pengenalan fagositik• Sel-sel apoptotik ekspresi fosfatidilserin dan trombospondin
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Morfologi• Cell shrinkage
• Chromatin condensation• Formation of cytoplasmic blebs and
apoptotic bodies• Phagocytosis of apoptotic cells or cell
bodies, usually by macrophages
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Elektroforesis DNA yang diekstraksi
dari kultur selA. KONTROL
B. APOPTOSISC. NEKROSIS
DNA ladders
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APOPTOSIS: gambaran ultrastruktur
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Mekanisma Biologik1. Signaling pathways menginisiasi apoptosis2. Kontrol dan integrasi keseimbangan antara
molekul negatif (menghambat) dan molekul positif (memacu)
3. Fase eksekusi (common-execution phase) program kematian yang sesungguhnya (protease keluarga caspase)
4. Pembersihan sel-sel mati dengan fagositosis
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Gambaran skematik kejadian apoptosis
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Peristiwa mitokondrial dan pengaruh bcl-2 pada apoptosis
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Contoh Spesifik Apoptosis• Signal oleh reseptor dari keluarga Tumor
Necrosis Factor (TNFR)- Apoptosis dimediasi oleh Fas-Fas ligand- Apoptosis diinduksi oleh TNF
• Apoptosis akibat stimulasi limfosit T sitotoksik (CTL)
• Apoptosis sesudah hilangnya growth factor • Apoptosis yang dimediasi oleh kerusakan DNA
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Model: signal dimediasi Fas, aktivasi kaspase, dan induksi
signal kematian
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Model signal dimediasi reseptor TNF dan induksi apoptosis: apoptosis vs survival
diinduksi TNF
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KESIMPULAN• Apoptosis merupakan proses faali
penting dalam tubuh yang dapat juga dipicu oleh penyebab patologik
• Apoptosis memegang peran penting dalam kejadian beberapa jenis penyakit, sebagai akibat disregulasi
• Apoptosis memegang peran penting dalam terapi, terutama terapi neoplasma dengan kemoterapi dan radioterapi
• Apoptosis makin penting dalam riset biomedik