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71 Cards in this Set

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What are the eary stages of hypoxic cell injury?
1) Decreased ATP synthesis
--failure of Na/K ATPase pump so get influx of Na and H20 from EC space

--hydropic change/cell swelling
--ER & mitochondrial swelling

2) disaggregation of ribosomes and failed protein synthesis
Late stage of hypoxic cell injury
1) membrane damage to plasma and to lysosomal organelle membranes
--MYELIN FIGURES=cytoplasmic bodies in damaged cells made of whorls of membranes from damaged cytoplasmic organelles...taken up into autophagosomes

--cell blebs

2) Cell death: SIGNS
--irreversible damage to cell membranes
--Nuclear changes: Pyknosis, karyolysis, karyorrhexis

--enzymes like LDH (from ruptured RBCs) CPK (from cardiac or skeletal muscle), AST/ALT (from liver)
Coagulative necrosis
1)results from interruption of blood supply, denaturation of proteins

2) seen in organs supplied by end arteries with little collateral such as heart and kidney

3) General architecture same
Liquefactive necrosis
1) enzymatic liquification of necrotic tissue

2) usually in CNS

3) From interupted blood supply OR in area of bacterial infection
What is caseous necrosis?
seen most commonly in tuberculous & fungal granulomas

Architecture not preserved
Looks "cheese-like"
increased affinity for acidophilic dyes
fibrinoid necrosis
fibrin-like proteinatcious material deposited in walls of small BV's

often as part of immune-mediated vasculitis (or from AI dz like SLE)

looks smudgy pink in vascular walls
fat necrosis
Lipase and other lytic enzymes released from damaged pancreatic cells, and permeate fat cells

Usually occurs with acute pancreatitis

See acute imflammation, hemorrhage, calcium soap formation, clustering of lipen-laden macrophages
What is steatosis
accumulation of intracellular parencymal triglycerides

--most frequently in liver, heart and kidney

--have overproduction of fat, decreased use in cells, and dec mobilization from cells
metastatic calcification vs. dystrophic
metastatic= caused by hypercalcemia (most often from inc PTH)

dystrophic=occurs in previously damaged tissues
NOT caused by hypercalcemia
Inflammatory processes
1) exudation of fluid from vessels

2)attraction of leukocytes to injury so they can engulf and destroy

3) activation of chemical mediators

4) proteolytic degredation of extracellular debris

5) restoration of injured tissue to normal function
inflammatory adhesion molecules
1) induced by IL-1 and TNF
L-selectins on neutrophils bind endothelial mucin-like molecules

E and P selectins on endothelial cells bind to surface of leukocytes

P-selectins in weibel-Palade bodies and platelet alpha granules --> go to plasma membrane after stimulated by histamine or thrombin
inflammatory adhesion molecules:ICAMS
ICAM-1 and ICAM-2=
expressed on endothelial cells and bind to integrin molecules on leukocytes

expressed on endothelial cells and bind to integrin molecules on leukocytes
vasoactive changes in acute inflammation
First have brief vasoconstriction, then dilation (get increased blood flow to affected)
increased capillary permeability in acute inflammation
causes leakage of proteinaceous fluid which causes edema

caused by endothelial changes
arrive during first 24 hours
--bacterial infections
--infarction or other causes of acute inflammation

**Note that early release of neutrophils is from the bone marrow reserve
replace neutrophils after 2-3 days

can engulf large particles and can divide & proliferate within inflamed tissue
viral infections (influenza, rubella, mono)
also see in TB
allergic reations
parasitic infections

also, hodgkins and polyarteritis nodosa)
mast cells and basophils
sources of histamine

see with CML and other myeloproliferative dzs
How do cells respond to leukocytes?
1) emigration
(leukocytes to outer margin of blood flow adjacent to endothelium)

(leukocytes line endothelial surface)

(endothelial selecins loosely bind leukocytes and help roll along endothelial surface

mediated by ICAMs and integrins

leukocytes move across endothelium
mediated by PECAM-1 on leukocytes and endothelium
process by which leukocytes move towards injury

chemotactic factors for neutrophils include:
1) products from bacteria
2)compllement components (C5a)
3)arachidonic acid metabolites (LTB4, HETE, and kallikrein)
facilitates phagocytosis by coating with opsonins which help immobolize particles on surface of phagocyte

Types of opsonins:
2) C3b
oxygen-dept microbial killing
myleoperoxidase halide:
If you have both leukocyte enzyme myeloperoxidase and halide ion like chloride, H202 will oxidize microbial proteins and distrupt the cell walls.
oxygen independent microbial killing
much less effective
mediated by:
lysozyme, MBP of eosinophils
Endogenous mediators: vasoactive amines
1) histamine--> causes increased capillary permeability

--from basophils, mast cells and platelets
Endogenous mediators: arachidonic acid metabolites
phospholipase A2 is what stimulates release of arachidonic acid from membrane phospholipids.

1) COX pathway yields
-- platelet TxA2--
vasoconstrictor and platelet aggregant

-- endothelial PGI2--
inhibits platelet aggregation

2) lipoxygenase pathway
yields HPETE
gives rise to leukotrienes (LTB4-chemotactic for neutrophils)
Endogenous mediators: cytokines
effector melecules that can influence other cells
immune response (INF-gamma)
inflammation (IL-1 and TNF)

Produce acute phase responses:
--systemic fever
--hepatic synthesis of:
CRP, amyloid, complement, fibrinogen, PT, ferritin, ceruloplasmin
--synthesis of adhesion molecules
--neutrophil degranulation
Endogenous mediators: kinin system
activated by Hageman factor (XIIa), which LINKS the kinin, coag, plasminogen, and complement systems!!

XIIa also activates kallikrein, which converts HMWK to bradykinin which controls vascular permeability
Endogenous mediators: complement system
C3a & C5a=anaphalotoxins--mediate degranulation of basophils and mast cells to release histamine


C5b-9=Membrane attack complex (MAC)(lytic for bacteria)
Endogenous mediators: Nitric oxide
--produced by endothelial cells

--stimulaties relaxation of smooth muscle which helps control vascular tone

--inhibits platelet aggregation, contributing to thromboresistance
Outcome of acute inflammation
(other than resolution)
cavity filled with PUS(neutrophils, monocytes and liquefied cell debris)

--results from tissue destruction by lysosomal products and other degradative enzymes

--usually caused by bacterial infections like staph

5) conversion to chronic inflammation:
--PMNs replaced by macs, lymphocytes etc
--new vessels and fibroblasts
Hereditary defects that impair acute inflammatory response
1) complement deficiency

2)chronic granulomatous DZ of childhood
=deficient NADPH oxidase

=phagocytic cells ingest but can't kill catalase + organisms (like staph)
H2O2 is destroyed and therefore can't use as a substrate for myeloperoxidase system

(note: in catalase neg, enough H202 is made by bacteria, so myeloperox can use this as its substrate

3)myeloperoxisdase deficiency

4) chediak Higashi syndrome (WBCs have abnormal MT formation, so impaired chemotaxis and migration)

5) LAD types 1 & 2
Chronic non-specific inflammation
1) interaction between macs and lymphocytes

2)fibroblast proliferation + new vessels

Granulomatous inflammation
1)granulomas=collection of macs called epitheliod cells

2) T-cell lymphocytes activate macs, causing release of cytokines (INF-gamma)

3)have multinucleated giant cells derived from macs

4) caused by:
--TB, leprae, histoplasma
--foreign bodies
--sarcoidosis (unknown cause)
3) Often see with CASEOUS NECROSIS
Cell repair: Cell proliferation
--promotes migration of fibroblasts and SM cells
--chemotactic for monocytes

2) EGF (epidermal GF)
--promotes growth of endothelial cells and fibroblasts

3) FGF's (fibroblast GF)
--promote ECM and fibronectin synthesis by fibroblasts, endothelial cells , monocytes.
--fibronectin promotes angiogenesis, and links cell surface integrins and ECM

4) TGF's (transforming GFs)
TGF-a is like EGF
TGF-b is growth inhibitor

5) mac-derived GF's= IL-1 & TNF
--promote prolif of fibroblasts, SM cells, and endothelial cells
Wound healing by primary Intention
Day 1) FIBRIN CLOT forms and neutrophils infiltrate wound margins

Day 2) MACROPHAGES emigrate into wound

Day 3)Formation of GRANULATION TISSUE=
--highly vascular, newly formed connective tissue made of capillaries + fibroblasts
--fills defects made by liquefaction

2 weeks=collagen compresses BV's in fibrous tissue, so dec blood flow

1 month=collegenase remodeling of wound
(ie, scar tissue formation)
what factors can delay/impede repair?
1)retention of debris

2) impaired circulation

3) persistent infection

4) metabolic dz like diabetes

5) glucocorticoids (interferes with collagen formation and dec tensile strength)

6)dietary deficiency of ascorbic acid or protein (needed for collagen formation)
hemorrhage terminology
1) hematoma--localized to tissue or organ

2) hemarthrosis--into synovial space

3) petechiae or purpura=
small hem. in skin, mucus membranes or serosal surfaces

diffuse hemorrhage in skin or sub-q
chronic passive congestion
-caused by LH failure or MV stenosis

-distension of alveolar capillaries can lead to rupture and passage of RBCs into alveoli

-phagocytosis of RBCs can result in intra-alveolar hemosiderin-laden mac's called heart-failure cells

most often by RH failure
Nutmeg liver=
from dilated congested central veins and fatty liver cells
Necrosis from ischemia caused by obstruction of blood supply

-white or pale, caused by arterial occlusions in heart, spleen and kidney

-red infarcts (RBVs ooze into necrotic area)

-see in LUNGS and GI TRACT

-can also be caused by venous occlusion (like incarcerated hernias, post-op adhesions)
Define Thrombosis and thrombogenesis
intravascular coag of blood causing significant interruption of flow

results from interaction of platelets, damaged endothelial cells and coag cascade
Functions of platelets
1) maintain physical integrity of vascular endothelium

2) endothelial repair through contribution of PDGF

3) from platelet plugs

4) promote coag cascade through platelet phospholipid complex
reactions involving platelets
1) Adhesion -
-vessel injury exposes subendothelial collagen
-glycoprot rec on platelets interacts with subendothelial collagen via: vWF

2) Release Reaction
platelets release ADP, histamine, 5-HT, PDFG

3) activation of coag cascade
conformational change in platelet membrane makes phospholipid complex available, leads to thrombin formation

4) Arachidonic acid metab
proceeds thru COX path to prod TxA2 (a vasoconstrictor and platelet aggregant.)

5)Platelet aggregation
recruit more platelets to produce inital PLUG
--this is promoted by ADP, thrombin, TxA2, collagen, epi, and PAF

6) stabilization of plpug
fibrinogen bridges bind aggregated platelets together, and this mass is stabilized by fibrin

7) limit of plug formation
PGI2 antagonizes TxA2 and limits further aggregation
Fibrin also inhibits aggregation
endothelial cells--function in coag
1)produce heparin like molecules that activate antithrombin III (this neutralizes thrombin and other coag factors

2) secrete TPA
3) degrade ADP
4) take up, inactivate a& clear thrombin

5)synthesize thrombomodulin--binds thrombin and converts it to APC
NOTE: APC cleaves factors Va and VIIIa, inhibiting coag!

6)synthesize protein S, cofactor for APC
7) releases PGI2
8) releases NO (acts like PGI2)
Coagulation: Extrinsic pathway
initiated by tissue factor

TF activates factor VII

VIIa activates factor X

Xa (with help of Va as cofactor) converts PT (II) to thrombin (IIa)

Thrombin converts fibrinogen-> fibrin
Coagulation: Instrinsic pathway
involves activation of all clotting factors except VII and XIII

***EVALUATE INTRINSIC BY PTT (partial thromboplastin time)
Fibrinolysis/ thrombus dissolution
-modulates coagulation

-restores blood flow in vessels blocked by thrombus

PLASMIN=most impt fibrinolytic protease
(splits fibrin)
Patterns of inflammation
1) Suppurative (purulent)
-local prolif of pus-forming organisms (abscess formation)

2) cellulitis
prolif of bacteria thru subcut tissue

3) Pseudomembranous
bacterial toxin-induced damage of mucosal lining

4) Fibrinous
inc vessel permeability with dep of fibrin-rich exudate along serosal surfaces

5) Ulceration
defect in epithelial lining of skin

6) Fistula
Lab findings associated with inflammation:
1)Acute inflammation:
-Absolute Neutrophilic Leukocytosis= rapid release of PMNs from bone marrow mediated by IL-1/TNF

-lots of asurophilic granules

-Left shift: >10% band PMNs or other precursors

2) Chronic inflammation
-absolute monocytosis
Lab findings associated with inflammation:
ESR=rate of settling of RBC's in a vertical tube in mm/hr

ESR is elevated in in acute or chronic inflammation

Increase ESR:
1)Plasma factor (inc fibrinogen which dec neg charge in RBCs)

2)RBC's (anemia)
Types of Edema
-transudate vs exudate
TRANSUDATE= protein-poor & cell-poor
--due to an INC in HYDROSTATIC pressure or DEC in ONCOTIC pressure

--produces pitting edema

EXUDATE=protein rich +cell rich fluid
--due to acute inflammation with inc vascular permeability

--have tissue swelling but no pitting edema
pulmonary thromboembolism &
arterial embolism
a detached mass (clot, fat, gas) carried thru blood to a distant site

1) Pulmonary thromboembolism
--most from femoral veins (or pelvic)
--only a few cause pulm infarction

2)Arterial embolism
--most from Left heart (mural thrombus, atrial myxoma etc)

--A-fib predisposes

-lower extremities
-brain via MCA (hemorrhagic infarcts)
-small bowel via SMA (hemorrhagic)
-spleen/kidneys-(pale infarcts)
Fat embolism
occurs after traumatic fracture of long bones (femur) or pelvis

-fat from bone marrow and adipose lodge in microvasculature
-fatty acids damage vessel endothelium, resulting in platelet thrombi

-see 24-72 hours post trauma

-CNS damage: ischemia, hemorrhage

-respiratory failure: hypoxemia

amniotic fluid embolism
tear in placental membranes--
infusion of amniotic fluid into maternal circulation and pulmonary vessels

-sudden onset of dyspnea, cyanosis, hypotensive shock
-maternal death in 80% of cases
decompression sickness
Inc atmos. pressure causes:
Nitrogen gas to move from alveoli through blood and dissolve in tissues

rapid ascent forces nitrogen gas bubbleds to develop in tissue and lumen of BV's

-muscle, joint, bone pain (the "bends")
-pulmonary embolism

aseptic necrosis in bones from bone infarctions
septic shock
mostly assoc with gram-neg infections (often e-coli)

1) endotoxins directly damage endothelial cells, causing release of NO & prostaglandin(vasodilators)

2) endotoxins activate alternative complement pathway, releaseing anaphalotoxins (C3a & C5a) ...more vasodilation of periph. resistance arterioles.

3) IL-1 & TNF released from macs, activate PMN-adhesion molecules

1)Increased Cardiac output initially, but tissue unable to remove O2 because of increased flow.

2)Dec LVEDV b/c of PMN emigration from pulm capillaries into alveoli
-warm skin from vasodilation
-increased CO,
-ARDS b/c PMN emigration into alveoli
-DIC from activation of coag system
Complications associated with shock
1) Ishcemic ATN
mostly PCT in cortex & tubular cells undergo coag necrosis leading to renal failure
**ATN can be reversible!!!

2) pulmonary edema

3) depeletion of lipid in adrenal cortex

4) hemorrhage in colon

5) centrilobular necrosis of liver

6) metabolic acidosis--
due to tissue hypoxia
-Glanzmann’s thrombasthenia
platelets won't stick together becuase of a mutation in Gp2b3a (needed for platelets to bind fibrinogen and adhere to each other)
Asbestosis-very fibrotic
1.Asbestosis: parenchymal fibrosis most severe fibrosis

2.Bronchogenic carcinoma, synergistic effect with cigarette use

3.Pleural effusions

4.Induces pleural fibrous plaques-restrictive lung disease

5.Diffuse pleural fibrosis

6.Mesotheliomas – rare neoplasm arising from mesothelial cells lining the pleura, cigarette smoking not a risk factor. (also house hold members who are exposed to individuals clothing with asbestos at risk)

7.Extrapulmonary neoplasms (Colon, larynx)

8.Serpentine: chrysotiles-most common form-not as harmful

9.Amphiboles: straight, brittle

10.Covered by iron

11.Lung cancer
--Bronchogenic CA
1. Silicone dioxide (ceramic industry)
2. Sandblasters
3. Slowly progressive
4. Nodular fibrosing pneumonitis-appear identical to very old granuloma (unless stain for silica)
5. Increased risk of TB
Coal Workers Pneumoconiosis
1. Anthracosis-carbon pigment in Mo
2. Simple coal workers’ pneumoconiosis-moderate deposition of C in lung (majority) minor to no symptoms
3. Progressive massive fibrosis-10%
Pneumoconiosis: occupational lung injury
Particle Size
1.>5 Trapped in nasal mucosa
2.3-5 um lodge in terminal bronchi/alveolill
3.1-2 um stay suspended in air ;cough out
4.Miner dusts
-Coal dust
5.Organic particles
6.Chemical fumes
7.Macrophage Phagocytosis
8.Macrophage activation
-Oxygen radicals, and proteases
-LTB4, IL-8, TNF, IL-6
-IL-1, PDGF, IGF-1, TGF-â: profibrotic
9.Chronic inflammation
Indoor Pollution
1. Carbon monoxide
2. Nitrogen Dioxide
3. Wood Smoke
4. Formaldehyde
5. Radon: second leading cause of lung cancer- in well insulated basements
6. Asbestos fibers
7. Manufactured mineral fibers
8. Bioaerosols
Tobacco Smoke
1.50% of all smokers will die of tobacco related disease
2.Lung disease
4.Cancer-carcinogenic properties of cigarettes
5.Chronic bronchitis emphysema
7.Systemic atherosclerosis
8.Bladder, pancreas, esophagus, larynx, and oral cavity cancers
9.Peptic ulcer
smoking continued...
second hand smoke
NOTE: On Xry should see bronchi lines ¨ö way through chest. Instead appears as dead space (hyperinflated due to damage) ¡æ indicative of emphysema

NOTE: Inflammatory response activated by smoking. Neutrophils activated and release protease and ROS. ¥Á-1 antitrypsin moderates neutrophil activation preventing extensive damage

Second-hand Smoke
1.Responsible for
-3,000 lung cancer deaths/yr
-30,000 to 60,000 cardiac deaths/yr

2.Effects on the fetus
-Intrauterine growth retardation (IUGR)
-Spontaneous abortion due to vasospasms
1.Nuclear, aerospace industry
2.Acute pneumonitis
3.Pulmonary and Systemic granulomas
-Lymphocyes (no exudate)
-Macrophages –giant cells
Chemical Injury

2.Requirement for metabolic conversion

3.Sites of absorption, accumulation, excretion

4.Individual variation

5.Capacity of agent to induce immunologic response
1.Endometrial carcinoma (unopposed estrogen)

2.Breast Cancer

3.Thromboembolism: factor V mutants (2-15% of population)

4.Cardiovascular disease-beneficial

5.Ovarian cancer-protective

6.Estrogens increase the risk of:
--Endometrial cancer
--Breast cancer

7.Recent studies have suggested that estrogens fail to protect women from cardiovascular disease
Oral Contraceptives
1.Breast cancer: slight or no risk in absence of BRCA mutations

2.Endometrial cancer: no increase risk

3.Ovarian cancer: protective, have actually been prescribed to individuals with BRCA1 mutations

4.Thromboembolism:risk, increased synthesis of coagulation factors, decreased protein C, particularly in older females who smoke


6.Hepatic adenoma: increased risk

7.Gallbladder disease: slightly increased risk

8.Does not increase risk, may decrease
1.Acetaminophen: hepatic necrosis

2.Aspirin (Acetylsalicylic acid)
--Respiratory alkalosis --> metabolic acidosis
-10-30g in adults: 2-4g in children
-Chronic toxicity 3g/d
**Erosive gastritis
Differences between benign and malignant tumors?
1) anaplasia= poorly differentiated


3)hyperchromatism=darkly staining nuclei

4)inc. nuc-cytoplasmic ratio

5) prominent nucleoli