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Cellular injury, Inflammation, adaptation, cell injury, Amyloidosis, free…
Cellular injury
Inflammation
acute inflammation
neutrophil, innate immune system
edema
mediators: Toll-like receptor, arachidonic acid metabolite, neutrophil, eosinophil, antibody, mast cell, basophil, complement, factorⅫ
inflammasome: activation of IL-1 and inflammatory responce
vasolidation(↑endothelial permeability), extravasation of leukocyte (margination, rolling, adhesion, transmigrant, migration)
outcome: resolution and healing(IL-10, TGF-β), persistent(IL-8), abscess, chronic inflammation, scarring
chronic inflammation
prolonged duration, infiltration by mononuclear cell, angiogenesis and fibrosis
type4, autoimmune disease, prolonged exposure
macrophage is dominant; IFN-γ(from Th1)→macrophage classical activation; IL-4,13(from Th2)→macrophage alternative activation
outcome: scarring, amyloidosis, neoplastic transformation(eg. HCV→hepatocellular carcinoma, H.pylori→gastric adenocarcinoma)
granulomatous disease
mycobacterium, CGD, sarcoidosis, Crohn disease, primary biliary cholangitis(原発性胆汁性胆管炎), subacute thyroiditis, GPA, EGPA, , ,
epitheloid cell(macrophage with pink cytoplasm) with multinucleated giant cell and lymphocyte
TNF-α activate macrophage, induce and maintain granuloma
sarcoidosis, noncaseating necrosis
TB, caseating necrosis
cardinal sign
tumor; swelling
↑vascular permeability, ↑oncotic pressure (leukotrienes, histamine, serotonin)
dolor; pain
sensitization (bradykinin, PGE₂)
ruber; redness(発赤), color; warmth(発熱)
vasolidation (histamine, prostaglandin, bradykinin)
functio laesa; loss of function(機能障害)
impair function
leukocyte extravasation
adhesion
vasculature: ICAM-1, VCAM-1
leukocyte: CD11/18 integrin, VLA-4 integrin
migration
travel through interstitium to site of injury or infection
to C5a, IL-8, LTB₄, kallikrein, platelet-activating factor
margination and rolling
vasculature: E-selectin, P-selectin, GlyCAM-1, CD34
leukocyte: Sialyl-Lewis, L-selectin
diapedesis(transmigration)
:both: PECAM-1
travel between endothelial cell
systemic manifestation
leukocytosis
leukemoid reaction: severe >40000WBC
↑plasma acute phage protein
fever
IL-1 and TNF (macrophage)→↑COX (perivascular cells of hypothalamus)→↑PGE₂→↑temperature
acute phage reactant
positive
serum amyloid A: lead to amyloidosis
hepcidin: ↓iron absorption and release; lead to anemia
fibrinogen: coagulation factor
C-reactive protein: opsonin, nonspecific
ferritin: bind and sequester iron
negative
albumin
transferrin
erythrocyte sedimentation rate(赤血球沈降速度)
product of inflammation coat RBC and cause aggregation, denser→faster→↑ESR
response to eliminate initial cause of cell injury, to remove necrotic cells resulting from original insult, and to initiate tissue repair
acute and chronic
adaptation
metaplasia
eg. Barrett esophagus or respiratory stratified squamous epithelium
malignant transformation can occur
replacement of cell type by another
connective tissue metaplasia can occur (eg. myositis ossificans(骨化性筋炎)
dysplasia
disordered, precancerous epithelial growth
loss of uniformity of cell size and shape(pleomorphism), loss of tissue orientation, nuclear change
sever dysplasia can be irreversible and lead to carcinoma
atrophy
↓in tissue mass due to ↓in size and number of cell
causes include disuse, denervation, loss of blood supply, loss of hormonal stimulation, poor nutrition
hyperplasia
contraoled proliferation of stem cell and differentiated cell→↑ in number of cell
pathogenic hyperplasia(eg. endometrial(子宮内膜) hyperplasia), progress to dysplasia and cancer
hypertrophy
↑structural protein and organell→↑size of cell
cell injury
necrosis
intracellular component leak
gangrenous(壊疽性壊死)
after chronic ischemia
ischemia, superinfection
coagulative, liquefactive
coagulative(凝固壊死)
ischemia/infarct in most tissue (except brain)
injury denature enzyme→proteolysis blocked
preserved architecture but cell disappear (↑eosinophilia)
fat(脂肪壊死)
lipase→saponification(けん化)
fat cell without peripheral nuclei, saponification of fat
acute pancreatitis, traumatic
fibrinoid(フィブリノイド壊死)
immune complex combine with fibrin (type3)
vessel walls are thick and pink
immunoreaction in vessels, preeclampsia(子癇), hypertensive emergency
liquefactive(液化壊死)
lysosomal enzyme from neutrophil digest tissue
cellular dibris and macrophage→cystic space and cavitation
brain infarct
caseous(乾酪壊死)
TB
granular debris
fragmented cells and debris surrounded by lymphocyte and macrophage(granuloma)
apotosisi
2 pathway activate caspase→cellar breakdown(including cell shrinkage, chromatin condensation, membrane bledding, formation of apoptotic body→phagocytosed
characterized by: eosinophilic cytoplasm, basophilic nucleus, pyknosis, karyorrhexis
ATP-dependent programmed cell death
DNA laddering is a sensitive indication of apotosis
intrinsic pathway
Bcl-2 prevent release of cytochrom C→tumorgenesis
DNA activation→p53→BAX and BAL→release of cytochrome C from mitochondrial membrane→activation of caspase
extrinsic pathway
ligand receptor interaction (FasL bind to Fas, TNF-α bind to receptor)
immune cell(cytotoxic T cell release of perforin and granzyme B)
defective Fas-FasL cause autoimmune lymphoproliferative syndrome
ischemia
brain (ACA,MCA,PCA boundary area), heart(LV), kidney, liver, colon are vulnerable
inadequate blood supply to meet demand
type of infarct
pale: solid organ with single blood suply (eg. heart, kidney, spleen)
red: venous occlusion, tissue with multiple blood supplies (eg. liver, lung, intestine), reperfusion
process
cellular/mitochondrial swelling, rebosomal/polysomal detachment, membrane blebbing, nuclear chromatin clumping(塊になる)
rupture of lysosomes and autolysis, nucleus pyknosis(condensation)/ karyorrhexis(fragmentation)/ karyolysis(fading), mitochondrial permeability, plasma membrane damage
cell death
Amyloidosis
localized
Alzheimer disease; β-amyloid protein
type 2 diabetes mellitus: islet amyloid polypeptide(IAPP)
medullary thyroid cancer(甲状腺髄様癌): calcitonin
isolated atrial amyloidosis: ANP
systemic senile amyloidosis: normal transthyretin, cardiac ventricles
systemic
secondary amyloidosis
AA
in chronic inflammatory condition, eg. rheumatoid arthritis, IBD, familial mediterranean fever, protracted infection
dialysis-related amyloidosis(透析アミロイドーシス)
β₂-microglobulin
end stage renal disease(ESRD)
primary amyloidosis
AL
plasma cell disorder and multiple myeloma
manifestation: cardiac, GI, renal, hematologic, neurologic, muscuskeletal
hereditary
familial amyloid cardiomyopathy: mutated transthyrctin(ATTR)
familial amyloid polyneuropathy: mutated transthyretin(ATTR)
abnormal aggregation of protein into β-pleated linear sheet
Congo red stain, polarized light(apple green), H&E stain(show deposit)
free radical injury
eliminated by scavenging enzyme, spontaneous decay, antioxidant, certain metal carrier protein
eg. oxigen toxicity (retinopathy, bronchopulmonary dysplasia, reperfusion), drug/chemical toxicity, metal storage disease(wilson disease, hemochromatosis)
membrane lipid peroxidation, protein modification, DNA breakage
radiation exposure, metabolism of drug, redox reaction, nitric oxide, WBC oxidative burst, transition metals
lipofuscin
yellow-brown pigment
formed by oxidation and polymerization of autophagocyted organellar membrane
associat with normal aging
scar formation
keloid: ↑↑↑collagen synthesis(type1 and 3), disorganized collagen synthesis, extend beyond border (on earlobe, face, upper extremities), frequent recurrence
nonregenerated cells are replaced by connective tissue
hypertrophic: ↑collagen synthesis(type3), parallel collagen organization, confined extent
exudate vs transudate
exudate(滲出)
↑protein
eg. lymphatic obstruction, inflammation, malignancy
cellular
transudate(滲出)
↓protein
↑hydrostatic pressure, ↓oncotic pressure
hypocellular
criteria
pleural effusion/surum protein ratio >0.5
LDH ratio >0.6
pleural effusion LDH>2/3 of the upper limit of normal for serum LDH
calcification
metastatic(転移性)
in normal tissue
widespread (eg. calcification of aleveolar walls in acute pneumonitis
abnormal serum Ca²⁺ level
in interstinal tissue of kidney, lung, gastric mucosa
in kidney, lead to nephrogenic diabetes insipidus and renal failure
2°to hypercalcemia or high calcium-phosphate product
dystrophic(異栄養性)
2° to injury or necrosis
granulomatous infection, liquefactive necrosis, fat necrosis, infract, thrombi, etc
tend ti be localized (eg. calcific aortic stenosis)
in abnormal tissue
wound healing
mediators
VEGF: angiogenesis
PDGF: vascular remodeling, smooth muscle cell migration, fibroblast growth (from platelet and macrophage)
TGF-β: angiogenesis, fibrosis
metalloproteinase: tissue remodelling
FGF: stimulate angiogenesis
EGF stimulate cell growth via tyrosine kinase
phase
proliferative (day3 to weeks)
fibroblast, myofibroblast, endothelial cell, keratinocyte, macrophage
delayed in vitamin C deficiency and copper deficiency
granulation tissue, type3 collagen, angiogenesis, epithelial cell proliferation, dissolution of clot, wound contraction
remodeling(week to 6 months)
fibroblast
type 1 collagen
delayed in zine deficiency
inflammatory (up to 3 days)
platelet, neutrophil, macrophage
clot formation, ↑vessel permeability, macrophage clear debris