kmr/Cell-Adap/111

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 / organInteraksi 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 injuryJenis & derajat stimuli

Stimuli 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 / didapatWaktu hidup lama dg akumulasi injury

sublethal

Respon selulerAdaptasi seluler

Hiperplasia, hipertrofiAtrofiMetaplasia

Cell injury :Injury reversible akutIrrebersible injury cell death

Nekrosis Apoptosis

Perubahan subseluler bbrp organela

Akumulasi intraseluler,kalsifikasiCelluler aging

kmr/Cell-Adap/1110

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 endometriumHiperplasia 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/1114

HIPERTROFI (2)Gen yg terlibat :

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

GF : TGF-β, IGF-1, Fibroblast GFAgen Vasoaktif : α-adrenergic agonist,

endothelin-1, angiotensin II

Hiperplasia & hipertrofi sering terjadi bersamaan

kmr/Cell-Adap/1115

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 atrofiǾ 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. & fungsitanda-2 : fosforilasi oksidatif ↓

adenosin trifosfat (ATP) ↓ pembengkakan sel : ok

perub konsentrasi ionair 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/1125Downloaded 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 selIntiMembran plasmaIsi sel

Reaksi radang sekitarFungsi fisio /

patologik

Membesar / swellingPyknosis karyolysisPecah / disruptedPencernakan

enzimatik,Sel bocorSeringPatologik,

bervariasi :fase akhir dr injury sel yg irreversible

kmr/Cell-Adap/11 29

ApoptosisMengecil /shrinkageFragmentasiUtuh/intact, perubahan

struktur : lemak

Utuh; lepas sbgai apoptotic bodies

Tidak 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 ApoptosisCell 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 kardiorespirasiPe ↓ kapasitas pengangkutan oksigen

anemia, keracunan CO

2. Bahan fisik :Trauma mekanisSuhu ekstrim (panas / dingin)

3. Bahan kimia / obat :Larutan hipertonikOksigen konsentrasi tinggi

kmr/Cell-Adap/11 32

Causa Cell injury (2)Racun : arsen, sianid, garam merkuriLain-2 : polutan, insektisid, herbisid, Produk industri : CO, asbesAlkohol & narkoba.

4. Bahan infeksious :Virus – bakteri – jamur – parasit (cacing pita)

5. Reaksi imunologik :Reaksi anafilaksisReaksi autoimun

kmr/Cell-Adap/11 33

Causa Cell injury (3)6. Kelainan genetik :

Down syndromeSickle cell anemia

7. Ketidak seimbangan nutrisi :Defisiensi protein-kaloriDefisiensi vitaminLipid berlebihan : obesitas, atherosclerosisPenyakit metabolik : diabetes

kmr/Cell-Adap/11 34

Mekanisme Cell injuryMekanisme 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 & NekrosisSel sakit reversible : (mikroskopik )

Celluler swelling = pembengkakan / edema / hidropik / degen. vacuolarFatty 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 enzimMerupakan 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.

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

kmr/Cell-Adap/11 49

Figure 1-12 Mitochondrial dysfunction in cell injury.

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

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

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

kmr/Cell-Adap/11 51

Figure 1-16 Timing of biochemical and morphologic changes in cell injury.

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

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:01 AM)© 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).Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:01 AM)

© 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.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:01 AM)© 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.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:01 AM)© 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.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:01 AM)© 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.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:01 AM)© 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.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 February 2005 02:01 AM)© 2005 Elsevier

Terima kasih

kmr/Cell-Adap/11 59