BMS Exam 2: Cell injury, inflammation & tissue repair

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BMS Exam 2

list possible etiologies of cell injury

hypoxia
physical agents
chemical agents & drugs
infectious agents
immunological reactions
genetic derangements
nutritional imbalances

list outcomes of cellular stress

- cellular adaptation: new altered steady state for cell
- cell injury: occurs when limits of cellular adaptation are exceeded

4 cellular systems & processes prone to injury

cell membrane integrity
aerobic respiration
enzyme & structural protein synthesis
nuclear integrity

4 important biochemical themes common to cell injury & cell death

Δs in membrane permeability
ATP depletion
O2 & O2-derived free radicals
Intracellular Ca+2 homeostasis

List cellular effects due to injury?

cellular swelling
abnormal lipid accumulation
hyperglycemia
abnormal pigment accumulation
hemosiderin
calcification
hyaline infiltration

cellular swelling

hypoxia → ↓ATP production 2° ↓Na-K ATPase pump activity

abnormal lipid accumulation

steatosis → abnormal parenchymal accumulations of → triglycerides or cholesterol (Esp. Liver)

Define Hyperglycemia & what tissues/organs does it commonly affect?

Occurs in abnormalities of glucose metabolism (e.g. Diabetes Mellitus)

Commonly affects: blood vessels, eyes, heart, kidneys, nervous tissue

abnormal pigment accumulations

-lipofuscin - atrophied/chronically injured cells
-- free radical & lipid peroxidation

- melanin: normal pigment turns bad
--melanoma --> local melanocyte change
--Addison's Dz --> diffuse melanocyte response to ↑[ACTH]

hemosiderin

- insoluble form of Fe in tissue
- abnormal accumulations (eg ↑ [Fe], impaired Fe utilization, hemolytic anemias) --> tissue staining
ex: bruise- Hb breakdown releases Fe bound in tissue by hemosiderin

calcification

Ca+2 may precipitate in:
areas of chronic inflammation
dead or degenerating tissue

hyaline infiltration

protein deposition secondary to long-standing HTN and DM

List morphologic changes due to injury

atrophy
hypertrophy
hyperplasia
dysplasia
metaplasia
anaplasia
neoplasia

atrophy

↓ cell size secondary -
↓ workload
↓ innervation
↓ blood supply
↓ nutrition or hormone stimulation

physiologic atrophy - 2° ↑ age

disuse atophy - ↓ use

hypertrophy

↑ cell size 2° to ↑ workload

hyperplasia

↑ tissue mass 2° ↑ # of cells

dysplasia

microscopic Δ in cell size or shape w/ loss of normal architecture

controlled reproduction of cells but may be related to malignant transformation

define metaplasia and give one example of this

- one cell 'type' replaced by another cell type
- usually a reversible Δ
- may be related to malignancy

ex: smokers - ciliated pseudostratified columnar epithelium replaced by stratified squamous epithelium in the larynx

anaplasia

- abnormal appearing cells lacking differentiation
- equated w/ undifferentiated malignant neoplasms

neoplasia

excessive uncontrolled clonal cell proliferation

list causes of anoxic cell injury/death

ischemia
thromosis
embolism

ischemia

- O2 requirement > O2 supply, tissue starving for O2
- reversible if blood flow restored
- atherosclerosis - most common cause
- may precede infarction or tissue death

thrombosis

- blood clot formations on intimal lining of blood vessels or heart
- most common cause: intimal disruption exposing subendothelial collagen

define embolism & identifiy sources

- free floating particle in blood stream lodges in blood vessel & occludes blood flow
- thrombus - most common source, it can get dislodged
- may also occur from: fat, heart valve vegetations or foreign bodies (FAT BAT)
Fat
Air
Thrombus
Bacteria
Amniotic Fluid
Tumor

define infarction, red (hemorrhagic) infarction, pale infarction

infarction: localized area of tissue 2° ↓ blood flow

red (hemorrhagic) infarction: occurs in loose tissues w/ blood collaterals (lung, intestines)

pale infarction: occurs in solid tissues w/ single blood supply (brain, heart, kidney, spleen)

define necrosis

cell or tissue death w/ morphologic evidence of death

define coagulative (fibrous) necrosis

coagulation occurs in infarcted area --> homogenous mass deprived of blood

liquefactive necrosis

liquefication of tissue due to autolysis or bacterial breakdown

characterized as wet, juice, slimy

gangrenous necrosis

"dry" gangrene - loss of blood supply
"wet" gangrene - liquefaction
"gas gangrene - spcefic type of necrosis due to Clostridia infections

apoptosis

-highly controlled, orderly process of cellular self-destruction
- involves coordinated destruction of intracellular structures by caspases
- celular stresses - activation of caspases

pathology of apoptosis

- caspase activation causes mitochondria to release cyctochrome c
- cytochrome c formation of an apoptosome
- apoptosome activates other caspases --> intracellular protease activity --> cell death

define acute inflammation & 4 cardinal signs

what is the hallmark of acute inflammation?

destroys, dilutes & walls off injurious agents
- major Δ = vasolidation
- ↑ blood flow → rubor & color
- ↑ vascular permeability → interstitial exudate

4 cardinal signs:
- rubor (redness)
- calor (heat)
- dolor (pain)
- tumor (swelling)
- (loss of function)

hallmark of acute inflammation: edema

** define exudation & exudate **

exudation: process where fluid, proteins & blood cells 'leak thru' vascular system to interstitial tissue

exudate: extravascular fluid that contains cellular debris & ↑ [protein]
specific gravity > 1.020

pus

purulent exudate with
↑ [WBC]
parenchymal cell debris

lymphatics

- lymph flow ↑ during inflammation
- also transport WBCs, cell debris, injuring agent

lymphangitis & "streaking"

lymphangitis - inflammation of lymph vessels

"streaking" - inflammation of lymph channel (see cell injury lecture pg 16)

lymphadenitis

inflammation of lymph nodes

what are the positive and negative factors of delivery of WBCs

positive factors:
- phaocytosis
- kills micrboes
- degrades necrotic tissue & foreign Ag

negative factors:
- prolongs → inflammation
- induces tissue damage (by attacking normal, healthy tissues)

process of WBC delivery

-margination, rolling, adhesions
- deapedesis
- migration toward chemotactic factors
- chemotaxis → WBCs migrate along chemical gradient

what are chemotactic factors for the delivery of WBCs

bacterial products
complement components
lipoxygenase products
cytokines

What are the predominant WBC types in the 1st 24 hours, and more than 24 hours

1st 24hours - neutrophils (first line of defense)
> 24 hours - monocytes

Recognition & attachment in Phagocytosis

- microogranisms are typically coated by opsonins (Fc fragment or C3b)
- opsonins bind to WBC receptors
- bacterial lipopolysaccharides (LPS) bind directly to WBC

oxidative & non oxidative mechanism of phagocytosis

oxidative mechanisms:
- O2-, H2O2, HOCl, -OH produced in phagolysosome via NADPH oxidase
- myeloperoxidase (MPO) produces hypochlorous acid (HOCl)

non-oxidative mechanisms:
-lysosomal enzymes

list the cell-derived chemical mediators that cause inflammatory response to occur

focus:
histamine
eicosanoids
cytokines
tumor necrosis factor

others:
serotonin
platelet activating factor
nitric oxide
many, many others

list plasma-derived mediators that cause inflammatory response to occur

Factor XII (Hageman Factor)
Bradykinin
Complement (C3a, C5a)

Histamine

cell-derived chemical mediator
- mostly found in mast cells and basophils
- performed & stored in granules

**physiological effects**
EDEMA
- vasodilation
- "leaky" capillaries

eicosanoids

cell-derived chemical mediator
- cell membrane derived phopholipids are converted inro arachidonic acid
- transformed via 2 main enzyme pathways:
-- cyclooxygenase
-- lipoxygenase

**can manipulate this pharmacologically

cyclooxygenase (COX) derivatives

prostaglandins (PG)
- PGI (prostacyclin) - vasodilates
- PGE series - vasodilates
- PGF series - vasoconstricts
- induces fever and pain

Thromboxane (TX)
- cause platelet aggregation & vasoconstriction

lipoxygenase derivatives

leukotrines (LT)
- causes vasoconstriction, bronchospasm & ↑ vascular permeability
- chemotactic for WBC
- major products: HPETE, HETE, Di-OH ETE, lipoxins

What therapeutic agents and target sites to inhibit eicosanoids

see cell injury lecture pg 21
- Aspirin Indomethacin: inhibit cycloxygenase pathway → ∅ prostaglandings → ∅ pain

- New pharmacological agents? "non-steroidal" Leukotriene modifiers or blockers: inhibit lipoxygenase pathway → ∅ leukotriene
--useful for asthma, or intense vasoconstriction

- corticosteroids - block parent molecule of making arachindonic acid → anti-inflammatory → ↓ production of other products in cyclooxygenase and lipoxygenase pathway

What inhibits Prostaglandins (PG) and Thromboxane (TX)?

steroids and NSAIDS

What inhibits Leukotrienes?

steroids & LT modifiers (Zafirlukast - Accolate)

cytokines

mediator of inflammation

cell signaling molecules produced by WBCs & endothelium

induces WBC aggregation & primes cells for inflammatory effects

Tumor necrosis factor (TNF)

- regulates immune cells & stimulates acute phase reaction
- usually produced by activated macrophages
- induces fever, apoptosis, sepsis & cachexia

what inhibits Tumor necrosis factors? (TNF)?

TNF inhibitor
infliximab, etanercept & others
used in CHRONIC (not acute) inflammatory Dz's (RA, IBD)

Factor XII (Hagemen Factor)

Mediator of Inflammation

activated by platelets or exposed collagen turns on 3 systems
- kinin
- coagulation
- fibrinolysis

Bradykinin (Kinin system)

mediator of inflammation

induces -
vasodilation
↑ capillary permeability

complement

mediator of inflammation

complement: blood proteins that help w/ opsonization, chemotaxis & formation of the membrane attack complex

also forms anaphylatoxins C3a & C5a

anaphylatoxin effects

anaphylatoxins (C4a, C3a, C5a) -->
- chemotactic, stimulate immune responses
- suppress immune responses
- bronchoconstriction
- vasoconstriction
- edema

inflammation acute phase reactions

- fever, ↓ appetite & ↑ catabolism
- severe cases - hemodynamic Δs
- ↑ hepatic synthesis of: C-reactive protein (CRP), complement, coagulation poteins

Inflammation peripheral WBC Δ

leukocytosis
↑ # immature PMNs -
- "shift to the left"
- "left shift"
- "bandemia"

list post-inflammation outcomes

- complete resolution
- fibrosis
- abscess formation
- chronic inflammation

complete resolution

return of normal tissue
usually occurs w/ small or short lived injuries

fibrosis

- healing by CT replacement
- occurs after substantial tissue destruction
also occurs -
- in tissues that DO NOT regenerate
- w/ excessive fibrinous exudate

abscess formation

occurs w/ pyogenic (pus-producing) infections

chronic inflammation

occurs when acute response cannot be resolved 2° to
- persistence of injuring agent
- interference in healing process
- duration: weeks → months w/ simultaneous tissue healing & destruction
- serves to contain & remove an agent or process w/in a tissue
- tissue macrophages are major cell involved in process
- HALLMARK: destruction of parenchymal cells & stromal framework

granulomatous inflammation

distinct type of chronic inflammation in response to indigestible substances

predominant cell types
- macrophage w/ epithelial cell-like appearance & produces a granuloma

where does granulomatous inflammation occur?

chronic immune Dz
certain infections (eg TB)
foreign body response

wound healing

restoration of tissue integrity after injury

wounds undergo:
contraction
formation of granulation tissue
-- angiogenesis
-- cell proliferation
new extracellular matrix
scar formation
tissue regeneration

wound healing methods

1° intention
- wounds have → apposed edges
- wound type: lacerations, surgical incisions
- thin scar
- color Δs red → white ~ 3 months

2° intention
- wounds have largely separated edges
- wound type: crush, gouges, infected or chronic wounds
- large amounts of fibrin, necrotic debris & exudate → intense inflammation & large scar

wound healing complications

- reopening of wound from various causes dehiscence (wound that falls apart)
- keloid: scar w/ ↑ collagen formation
exuberant granulation: excessive granulation tissue

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