Adaptasi seluler

kmr/Cell-Adap/11

1

ADAPTASI SELULER

Karyono Mintaroem

kmr/Cell-Adap/11 2

Perubahan Morfologi

Perubahan morfologi = perubahan struktur sel / jaringan / organ

ciri-ciri penyakit / dx proses etiologik.

Perub. Morfo. + biomol + imunologik ciri-ciri pnykt / perjalanan pnykt / pndktn tx / prognosis lbh jelas.

kmr/Cell-Adap/11 3

Perubahan fungsi / manifestasi klinik

Fungsi normal symptoms & sign,

perjalanan pnykt,

prognosis.

Perubahan morfologi sel / jaringan / organ

Interaksi sel-sel / sel-matriks

kmr/Cell-Adap/11 4

Respon sel >< stres & stimuli yg berbahaya

(1)Program genetik

metabolisme, diferensiasi, spesialisasi

Sel tetangga Sel Normal ketersediaan

fungsi & struktur substrat metabolik

homeostasis

kmr/Cell-Adap/11 5

Sel adaptasi fisiologik homeostasis (baru) morfologik - tetap hidup - modulasi fungsi hiperplasi = Σ sel ↑ hipertrofi = Ǿ sel ↑ atrofi = Ǿ & fungsi sel ↓

metaplasia

Respon sel >< stres & stimuli yg berbahaya (3)

kmr/Cell-Adap/11 6

Respon sel >< stres & stimuli yg berbahaya

(4)Adaptasi gagal cell injury s/d batas tertentu: reversible

Stres ↑ ↑ point of no return

cell injury irreversible

cell death

kmr/Cell-Adap/11 7

Respon sel >< stres & stimuli yg berbahaya (2)

kmr/Cell-Adap/118

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 11 February 2005 04:43 PM)© 2005 Elsevier

kmr/Cell-Adap/11 9

Respon seluler terhadap injury

Jenis & derajat stimuliStimuli fisiologik yg berubah:

Demand ↑, Stimulasi trofik↑

Nutrien ↓, stimulasi ↓

Iritasi khronik (kimiawi, fisikal)

Suplai O2 ↓, injury kimia, infeksi mikroba :

Akut & self limited

Progresif & Berat (rusaknya DNA)

Injury ringan khronik

Perubahan metabolik, genetik / didapat

Waktu hidup lama dg akumulasi injury sublethal

Respon selulerAdaptasi seluler

Hiperplasia, hipertrofi

Atrofi

Metaplasia

Cell injury :

Injury reversible akut

Irrebersible injury cell death

Nekrosis

Apoptosis

Perubahan subseluler bbrp organela

Akumulasi intraseluler,kalsifikasi

Celluler aging

kmr/Cell-Adap/11

10

Adaptasi seluler pada pertumbuhan & diferensiasi

Bentuk adaptasi :hiperplasiahipertrofiatrofimetaplasia

Mekanisme molekulernya bermacam-macam

kmr/Cell-Adap/11

11

HIPERPLASIA (1)Σ sel pd organ/jaringan ↑ volume organ/jaringan ↑

Hiperplasia fisiologik :

Hiperplasia hormonal

Hiperplasia kompensatoir

Mekanisme hiperplasia : Produksi Growth Factor ↑ produksi Level GF Receptor ↑ faktor Aktivasi lintasan signal intraseluler transkripsi ↑

Aktivasi gen-gen seluler proliferasi sel

kmr/Cell-Adap/11

12

HIPERPLASIA (2)

Hiperplasia patologik :

Hiperplasia ok induksi hormonal >> :

Hiperplasia endometrium

Hiperplasia ok induksi GF >> :

Pada penyembuhan lukajar. parut (proliferasi fibroblast)

Infeksi virus : papilloma virus wart (hiperplasia epitelium)

kmr/Cell-Adap/1113

HIPERTROFI (1)

Ukuran sel ↑ ukuran organ ↑Tidak ada sel baru !!! Sintesa komponen struktural sel ↑DNA inti sel hipertrofi >> inti sel biasa

Mekanisme hipertrofi :a. Induksi hormonal : gland. Mamma, uterus.b. Mekanik : beban ↑, stretch : otot jantung, ORwan.

a+b lintasan signal transduksi induksi gen-2 stimulasi sintesa protein sel.

kmr/Cell-Adap/11

14

HIPERTROFI (2)

Gen yg terlibat :

Yg mengkode faktor transkripsi : c-fos, c-jun

GF : TGF-β, IGF-1, Fibroblast GF

Agen Vasoaktif : α-adrenergic agonist, endothelin-1, angiotensin II

Hiperplasia & hipertrofi sering terjadi bersamaan

kmr/Cell-Adap/11

15

kmr/Cell-Adap/11 16

ATROFI (1)

“Pengkerutan / pengecilan sel akibat hilangnya substansi sel”

Merupakan respon adaptasi yg bisa berakhir dengan kematian sel (cell death).

Atrofi fisiologik :pdu selama perkembangan awal, misal :

Kel. Thymus, ductus thyroglossus, pd dewasa / lanjut (senile atrophy), misal :

Uterus setelah persalinan, glan. mamma,epitel vagina, otak, jantung,

kmr/Cell-Adap/1117

ATROFI (2)Atrofi pathologik :

Lokal / general (sistemik) jenis causa.Beban ↓(atrophy of disuse) :

pd immobilisasi, mis : frakturInnervasi (-) = denervation atrophySuplai darah ↓(ischemia) : atrofi otak pd lansia.Nutrisi tak cukup : marasmus penyakit keradangan khronis cachexia kanker

kmr/Cell-Adap/11 18

ATROFI (3)

Penekanan (pressure) :

penekanan, wkt lama atrofi

Ǿ tu ↑ ↑ ischemik jar sekitar atrofi.

Pd sel otot yg atrofi :

mitochondria/myofilamen/e.r.: ↓ ↓.

Mekanisme atrofi : belum seluruhnya jelas.

“ degradsi protein oleh enzim-enzim / sitokin”

a.l.: lysosom, proteasom, TNF

19kmr/Cell-Adap/11

kmr/Cell-Adap/11 20

METAPLASIA (1)

“Pergantian satu jenis sel dewasa ke jenis sel dewasa yg lain & reversible”

Sel epitel maupun sel mesenchymal.

Contoh :epitel kolumnar bersilia epitel skuamous

bertatah : bronkhus, ok asap

rokokepitel kolumnar sektretorikepitel skuamous

bertatah : duktus kel. Liur, pankreas, d. choledochus ; ok batu

kmr/Cell-Adap/1121

METAPLASIA (2)

Epitel skuamousepitel kolumnar intestinal :

esofagus distal, : Barrett metaplasia.

Metaplasia jar. ikatcartilago, tulang, jar. lemak.

Contoh : pembentukan jar tulang didalam otot = myositis ossificans, fraktura

Mekanisme metaplasia :Pemrograman ulang stem cells yg sdh ada.signalstimuli sitokin, GF, komponen matriks ekstraselulerdiferensiasi stem cell.Melibatkan gen-2 pengatur diferensiasi.

22kmr/Cell-Adap/11

kmr/Cell-Adap/11 23

Cell injury & Cell deathSel sakit & sel mati (1)

Mekanisme :

Reversible cell injury :

stimuli yg merusak perub. morfo. & fungsi

tanda-2 : fosforilasi oksidatif ↓

adenosin trifosfat (ATP) ↓

pembengkakan sel : ok

perub konsentrasi ion

air masuk kedlm sel (water influx)

kmr/Cell-Adap/11 24

Cell injury & Cell deathSel sakit & sel mati (2)

Irreversible injury & cell death :

Stimuli ↑ ↑ kerusakan ↑ ↑ sel mati (irreversible)

Contoh : pd myocardium dg ischemia :

perub struktur pd mitochondria :

bhn amorf yg padat

perub fungsi mitochondria :

permeabilitas membran (-)

tanda sel mengalami injury irreversible

kmr/Cell-Adap/11

25Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 11 February 2005 04:43 PM)

© 2005 Elsevier

kmr/Cell-Adap/11 26Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 11 February 2005 04:43 PM)

© 2005 Elsevier

kmr/Cell-Adap/11 27Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 11 February 2005 04:43 PM)

© 2005 Elsevier

kmr/Cell-Adap/11 28

Nekrosis

Ukuran sel

Inti

Membran plasma

Isi sel

Reaksi radang sekitar

Fungsi fisio / patologik

Membesar / swelling

Pyknosis karyolysis

Pecah / disrupted

Pencernakan enzimatik,

Sel bocor

Sering

Patologik, bervariasi :

fase akhir dr injury sel yg irreversible

kmr/Cell-Adap/11 29

Apoptosis

Mengecil /shrinkageFragmentasiUtuh/intact, perubahan

struktur : lemak

Utuh; lepas sbgai

apoptotic bodiesTidak adaSering fisiologik :

eliminasi sel yg tidak perlu

Patologik : kerusakan DNA

Ukuran selIntiMembran plasma

Isi sel

Reaksi radang sekitarFungsi fisio / patologik

Features of Necrosis and Apoptosis

Feature Necrosis Apoptosis

Cell size Enlarged (swelling) Reduced (shrinkage)

Nucleus Pyknosis → karyorrhexis → karyolysis

Fragmentation into nucleosome-size fragments

Plasma membrane

Disrupted Intact; altered structure, especially orientation of lipids

Cellular contents

Enzymatic digestion; may leak out of cell

Intact; may be released in apoptotic bodies

Adjacent inflammation

Frequent No

Physiologic or pathologic role

Invariably pathologic (culmination of irreversible cell injury

Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage

kmr/Cell-Adap/11 31

Causa Cell injury (1)1. Kekurangan oksigen (hypoxia)

Kegagalan kardiorespirasi

Pe ↓ kapasitas pengangkutan oksigen

anemia, keracunan CO

2. Bahan fisik :

Trauma mekanis

Suhu ekstrim (panas / dingin)

3. Bahan kimia / obat :

Larutan hipertonik

Oksigen konsentrasi tinggi

kmr/Cell-Adap/11 32

Causa Cell injury (2)

Racun : arsen, sianid, garam merkuri

Lain-2 : polutan, insektisid, herbisid,

Produk industri : CO, asbes

Alkohol & narkoba.

4. Bahan infeksious :

Virus – bakteri – jamur – parasit (cacing pita)

5. Reaksi imunologik :

Reaksi anafilaksis

Reaksi autoimun

kmr/Cell-Adap/11 33

Causa Cell injury (3)

6. Kelainan genetik :

Down syndrome

Sickle cell anemia

7. Ketidak seimbangan nutrisi :

Defisiensi protein-kalori

Defisiensi vitamin

Lipid berlebihan : obesitas, atherosclerosis

Penyakit metabolik : diabetes

kmr/Cell-Adap/11 34

Mekanisme Cell injury

Mekanisme biokimiawi sel sakit: sangat kompleks.

3 prinsip :

1. Respon seluler tergantung pd : jenis injury,

lamanya, berat-ringannya.

2. Manifestasi tergantung pd : tipe, status dan kemampuan adaptasi sel yg mengalami injury.

3. Sel sakit merupakan akibat dr abnormalitas fungsi dan proses biokimiawi bbrp komponen penting dalam sel.

kmr/Cell-Adap/11 35

Mekanisme biokimia yg terjadi:(1)

1. Hilangnya ATP / menurunnya sintesa ATP.

pdu ok injury hipoksia / kimiawi toksik.

ATP perlu utk proses-2 sintesa / degradasi ;

sintesa protrin, membrane transport, lipogenesis, metab. fosfolipid., dll.

2. Kerusakan mitochondria.

ok : Ca++ sitosol ↑, stres oksidatif, terurainya fosfolipid, lepasnya cytochrome c ke sitosol.

kmr/Cell-Adap/11 36

Mekanisme biokimia yg terjadi (2)

3. Influx Ca intraseluler & gangguan homeostasis Ca

ok : ischemia, toksin.

Ca ↑, → Aktivasi enzim-2 al : ATPase, fosfolipase, protease, endonuclease.

Permeabilitas mitochondria ↑, → induksi apoptosis

4. Akumukasi radikal bebas derivat oksigen

(oxidative stress).

contoh : O2-*, H2O2, OH*.

kmr/Cell-Adap/11 37

Mekanisme biokimia yg terjadi (3)

5. Defek permeabilitas membran.

Yg terkena : membran plasma, membran mitochondria, dll.

Causa :

Membran plasma : toksin bakteri, protein virus, bhn fisikal / kimiawi.

Mitochondria : hipoxia, ATP↓.

Berkurangnya ATP

kmr/Cell-Adap/11 38

Disfungsi Mitochondria

kmr/Cell-Adap/11 39

Peningkatan Ca sitosolik

kmr/Cell-Adap/11 40

kmr/Cell-Adap/11 41

Morfologi Sel Sakit & Nekrosis

Sel sakit reversible : (mikroskopik )

Celluler swelling = pembengkakan / edema /

hidropik / degen. vacuolar

Fatty change = perlemakan

Fungsi membran plasma trgg → homeostasis cairan

& inti trgg → edema sel

Injury : hipoxia/toksik/metabolik → vacuola lipid didalam sitoplasma (fatty change)

kmr/Cell-Adap/11 42

Morfologi Sel Sakit reversible :

Makroskopik : pd organ

lebih pucat, turgor ↑, berat ↑.

Mikroskopik :

vakuola kecil, jernih (sulit dilihat).

kmr/Cell-Adap/11 43

Nekrosis (1)

Akibat dari : denaturasi protein intraseluler pencernakan enzimatik .Sel tampak lbh eosinofilik, homogen spt kaca

(glassy homogenous), vacuole dlm sitoplasma, kalsifikasi.

Perubahan-2 pd inti :karyolysis : chromatin memudar (basofilik /

kebiruan ↓)pyknosis : inti mengkerut, lbh basofilik.karyorrhexis : inti pyknotik → fragmentasi.

kmr/Cell-Adap/11 44

Nekrosis (2)

Nekrosis koagulatif : terutama ok denaturasi

Sel tampak acidofilik, tidak berinti, arsitektur Jaringan masih nampak (terutam bila ok hipoksia)

contoh : infark jantung, infark ginjal.

Nekrosis liquefaktif : terutama ok digestif enzim

Merupakan tanda infeksi bakteri, kadang jamur.

Apapun patogenesisnya, liquefaksi mencernak habis seluruh sel mati → massa liquid viskous.

Rad. Akut → lekosit mati↑ ↑ → massa :krim kekuningan=

pus

kmr/Cell-Adap/11 45

Nekrosis (3)

Nekrosis kaseosa :bentuk khusus nekrosis koagulatif.

Sering pd TBC. Caseous “cheesey white”.

Mikros : debris granuler, amorf (trdr fragmen sel-2 yg koagulatif), dikelilingi keradangan. “reaksi / keradangan granulomatous.

Arsitektur jaringan hilang.

Nekrosis lemak (Fat necrosis) :

Bukan pola/jenis nekrosis yg sebenarnya.

contoh : pancreatitis akut lipase keluar liquifaksi sel lemak.

kmr/Cell-Adap/11 46

Nekrosis (4)

Mikroskopik ;

bayangan sel lemak nekrotik, kalsium deposit basofilik, dikelilingi keradangan.

Makroskopik ;

daerah putih, seperti kapur (kalsium + asam lemak) = fat saponification.

kmr/Cell-Adap/11 47

Figure 1-10 Cellular and biochemical sites of damage in cell injury.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:00 AM)

© 2005 Elsevier

kmr/Cell-Adap/11 48Figure 1-11 Functional and morphologic consequences of decreased intracellular ATP during cell injury.


© 2005 Elsevier

kmr/Cell-Adap/11 50Figure 1-13 Sources and consequences of increased cytosolic calcium in cell injury. ATP, adenosine triphosphate.


© 2005 Elsevier

kmr/Cell-Adap/11 52

Figure 1-14 The role of reactive oxygen species in cell injury. O2 is converted to superoxide (O2-) by oxidative enzymes in the endoplasmic reticulum (ER), mitochondria, plasma membrane, peroxisomes, and cytosol. O2- is converted to H2O2 by dismutation and thence to OH by the Cu2+/Fe2+-catalyzed Fenton

reaction. H2O2 is also derived directly from oxidases in peroxisomes. Not shown is another potentially injurious radical, singlet oxygen. Resultant free radical damage to lipid (peroxidation), proteins, and DNA leads to various forms of cell injury. Note that superoxide catalyzes the reduction of Fe3+ to Fe2+,

thus enhancing OH generation by the Fenton reaction. The major antioxidant enzymes are superoxide dismutase (SOD), catalase, and glutathione peroxidase. GSH, reduced glutathione; GSSG, oxidized glutathione; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate.


© 2005 Elsevier

kmr/Cell-Adap/11 53

Figure 1-15 Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of

ischemic tissues, also cause membrane damage (not shown).


© 2005 Elsevier

kmr/Cell-Adap/1154

Figure 1-22 Postulated sequence of events in reversible and irreversible ischemic cell injury. Note that although reduced oxidative phosphorylation and ATP levels have a central role, ischemia can cause direct membrane

damage. ER, endoplasmic reticulum; CK, creatine kinase; LDH, lactate dehydrogenase; RNP, ribonucleoprotein.


© 2005 Elsevier

kmr/Cell-Adap/1155

Figure 1-18 Ischemic necrosis of the myocardium. A, Normal myocardium. B, Myocardium with coagulation necrosis (upper two thirds of figure), showing strongly eosinophilic anucleate myocardial fibers. Leukocytes in the

interstitium are an early reaction to necrotic muscle. Compare with A and with normal fibers in the lower part of the figure.


© 2005 Elsevier

kmr/Cell-Adap/1156

Figure 1-19 Coagulative and liquefactive necrosis. A, Kidney infarct exhibiting coagulative necrosis, with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture.

B, A focus of liquefactive necrosis in the kidney caused by fungal infection. The focus is filled with white cells and cellular debris, creating a renal abscess that obliterates the normal architecture.


© 2005 Elsevier

kmr/Cell-Adap/1157

Figure 1-20 A tuberculous lung with a large area of caseous necrosis. The caseous debris is yellow-white and cheesy.


© 2005 Elsevier

kmr/Cell-Adap/1158

Figure 1-21 Foci of fat necrosis with saponification in the mesentery. The areas of white chalky deposits represent calcium soap formation at sites of lipid breakdown.


© 2005 Elsevier

Terima kasih

kmr/Cell-Adap/11 59

Adaptasi seluler

Documents

Transcript of Adaptasi seluler