9/20 Flashcards
Cardinal Signs of Inflammation explained by Chemicals
1-2. Rubor/calor: vasodilation increases blood flow
Histamine, prostaglandins, and bradykinin relax arteriolar smooth muscle
- Tumor: fluid leakage from venules into interstitium (exudate)
Histamine causes endothelial cell contraction
- Dolor: bradykinin and PGE2, sensitive nerve endings
- Fever: pyrogens (LPS) cause IL-1 and TNF-alpha release from macrophage, increased cyclooxygenase activity in hypothalamus
Increased PGE2 raises temp. set point
Mediators of Endothelial Cell Activation
- Early activators: histamine, bradykinin, PAF, thrombin
Promote vasodilation and permeability
- Late Activators: IL-1beta, TNFalpha, IFNgamma
- Other mediators: Complement, bacterial products, hypoxia, viruses, prostaglandins, leukotrienes
Consequences of Endothelial Cell Activation
Transient vasoconstriction from endothelins, thromboxane, and angiotensin II
Vasodilation of precapillary arterioles that is caused by NO, PAF, bradykinin, PGI2
Increased vascular permeability, fluid and cells leave circulation
Release cytokines like IL-8 that promote neutrophil activation
Contraction of cytoplasmic myosin occurs early due to histamine, bradykinin, and leukotrienes, increase vascular permeability by increasing gap between endothelial cells
Retraction of cytoskeletal elements occurs later due to IL-1, INF-gamma, TNF-alpha
Transudate vs. Exudate
- Transudate: low protein content, essentially no leukocytes, no endothelial cell damage, clear liquid
Due to decreased protein synthesis like liver disease or increased protein loss like kidney disease
Allergic dermatitis, herpes
- Exudate: high protein content, has some WBCS and RBCs
Due to inflammation that causes vasodilation and increases interendothelial spaces, has Endothelial Cell damage
Cloudy liquid, fibrin rich, purulent, sanguineous
Starling’s Law and how Inflammation Impacts it
- Increased vascular permeability: slight increase in K
- Interendothelial gap formation: slight increase in K
Involves early contraction of cytoplasmic myosin that is then balanced later by a late retraction of cytoskeletal elements
- Direct Endothelial Cell Injury: large increase in K, severe monophasic increase in permeability
May be direct injury to vessel and can be fast/long lived
May be leukocyte-dependent injury, mostly venules/pulmonary capillaries, late response and is long lived
Steps in Neutrophil Arrival
- Margination: hemoconcentration where RBCs group in middle of vessel, WBC margination, vasodilation slows blood flow
- Rolling- Selectins (speed bumps) upregulated
P-selectin: Weibel-Palade bodies store them on ECs, released by histamine
E-selectin: induced by TNF and IL-1 - Adhesion: cellular adhesion molecules upregulated on endothelial cells by TNF and IL-1, integrins upregulated on leukocytes by C5a, CAM-Integrin interaction results in firm adhesion of leukocytes to endothelial cells
- Transmigration and chemotaxisneutrophils attracted by bacterial products, IL-8, C5a, LTB4
- Phagocytosis
- Resolution: neutrophils do apoptosis and die within a day of inflammation resolution
Cell Adhesion Molecules
P selectin on EC binds to leukocyte mucin carbs like sialyl-Lewis X residues, activated by histamine, PAF, and thrombin
E-selectin upregulated due to TNFalpha and IL-1beta
Integrins on leukocytes bind to ECM, VCAM-1, fibronectin, and fibrinogen
CAMs from immunoglobulin superfamily stimulated by TNFalpha and IL-1beta
Chemokines Dependent Leukocyte Activation
Low avidity integrins on Leukocyte bind to receptors on endothelial cell with chemokines on proteoglycans on cell surface
Activated ECs from TNF and IL-1 express new CAMs that bind to the high avidity integrins on activated leukocytes
Integrins are heterodimeric proteins
Leukocyte Paracellular Transmigration
Intracellular Adhesion molecule 1 (ICAM1) on EC binds macrophage antigen 1 (MAC1)
Triggers increased intracellular Ca2+, RHO, and p38 MAPK to increase myosin contractility and EC contractility
Beta-1 integrin and other proteases on Leukocyte help transmigrated between cells
Leukocyte transcellular transmigration
Go through thin parts of EC with actin and caveolae-rich regions, ICAM1 containing caveolae link together to form vesiculo-vacuolar organelles to form an intracellular channel, ERM proteins provide structural support between ICAM1 and EC actin
Go through pericyte gaps, may need MMP and neutrophil elastase activity to help move through basement membrane
Chemotaxis
Go along conc. gradient of chemotactic factors like C5a, IL-8, and PAF
Rapid actin polymerization at leading edge of leukocyte’s filopodia, integrins on surface help facilitate movement
NSAIDs basics
2 types: non-selective and selective/COX-2 inhibitors
Inhibition of COX-1 causes GIT toxicity, PGE has protective effects on gastric mucosa
COX-1: prostaglandins and thromboxanes
Gastroprotectiin, platelet aggregation, renal function
COX-2: prostaglandins
Pain, fever, renal function, tissue repair, reproduction, development
NSAIDs Types
COX-1/2 Inhibitors-
Aspirin
Ibuprofen: Motrin, Advil, osteoarthritis, rheumatoid arthritis
COX-2 Inhibitors-
Celecoxib: Celebrex, inflammation, osteoarthritis, rheumatoid arthritis
Meloxicam
Patent Ductus Arteriosus
Congenital heart disorder where neonate’s ductus arteriosus fails to close after birth
PDA remains open (patent), have improper mixing between oxygenated aorta blood and deoxygenated pulmonary artery blood
Congestive heart failure if untreated
Prostaglandin E1 keeps the ductus patent, use NSAIDs like indomethacin to help close
NSAIDs Pharmacological Effects
Analgesic
Antipyretic
Anti-inflammatory
Some are uricosuric
GIT damage like ulcers/gastritis (lack PGE1)
Aspirin
Acetylsalicylic acid, normally converted to salicylic acid by esterase
Aspirin irreversibly inhibits COX (1 and 2) by acetylation, most other NSAIDs are reversible inhibitors
Decrease synthesis of thromboxane A2 and prostaglandins, increase bleeding time, used for anti-platelet effects
Clinical Uses: Anti-inflammmatory Analgesic Antipyretic Anti-coagulant
Adverse Reactions-
GI: nausea, vomit, ulcers
CNS: tinnitus, hearing loss
Hematologic: increase bleeding time, thrombocytopenia (low platelet count)
Reye’s Syndrome: children problem
Pulmonary: asthma if aspirin hypersensitivity
Reye’s Syndrome
Acute encephalopathy and fatty degenerative liver failure (microvesicular fatty change)
Seen in children after viral infections
Symptoms: nausea, vomit, mental status change, encephalopathy, altered liver function
Aspirin shouldn’t be used in children
Kawasaki Syndrome
Autoimmune disease seen in kids under 5
Inflammation in walls of medium sized arteries including coronary arteries
Symptoms: fever, skin rashes, red eyes, strawberry tongue, sore throat, swollen palm/feet/lymph nodes
Treatment: high aspirin dose and IV gamma globulin, only time give kids aspirin
NSAIDs: Selective COX-2 Inhibitors
Analgesic, antipyretic, anti-inflammatory, doesn’t affect platelet aggregation
Preferred in patients with gastritis or ulcers, doesn’t inhibit PGE1
Higher risk of cardiovascular thrombotic events: decrease PGI2 (reduces platelet aggregation) and no effect on thromboxane (increase platelet aggregation)
Celecoxib: cardiovascular black box warning, sulfonamide so rashes
Meloxicam: treats osteoarthritis
Rofecoxib: selective COX-2 inhibitor that was withdrawn over safety concerns, heart attack and stroke from long term high doses, widely used
Acetaminophen (Tylenol)
Weak COX-1/2 inhibitor in peripheral tissues, not very good anti-inflammatory
Analgesic, antipyretic, use for moderate pain when don’t need anti-inflammatory, no effect on platelet function and no gastric problems
Give to kids instead of aspirin
Adverse Reactions: 15 g may be fatal due to severe hepatotoxicity
Antidote: N-Acetylcysteine, Tylenol broken down to toxic intermediate that needs glutathione intervention, high conc. of intermediate binds to liver proteins and causes hepatic cell death, antidote is glutathione substitute
Glucocorticoids
Most powerful anti-inflammatory
Cortisone, hydrocortisone, prednisone
Inhibits Phospholipase A2 and expression of COX-2
Anti-inflammatory and immunosuppressant, chronic use causes Cushing Syndrome
Side effects: hypertension, obesity, muscle weakness, moon fancies, skin ulcers, buffalo hump
Methotrexate
DMARD of choice to treat rheumatoid arthritis
Folic acid analog that inhibits dihydrofolate reductase and get less THF, less dTMP and then DNA synthesis
Clinical Use-
- Non-neoplastic: rheumatoid arthritis, abortion, ectopic pregnancy, psoriasis
- Cancer: leukemia, lymphoma, sarcomas
Toxicity-
- Myelosuppression, reversible with leucovorin
- Macrovesicular fatty change in liver
- Mucositis
- Teratogenic
Increased Hydrostatic Pressure
Value for capillary hydrostatic pressure increases, get edema from backup of venous blood, push more blood into interstitium
Impaired venous return: hepaticncirrhosis, pulmonary edema due to congestive heart failure
Venous Obstruction: lower limb inactivity (gravity), thrombosis, mass
Problems: ascites, pulmonary/peripheral/pitting edema
Ascites
Fluid accumulation in the abdominal cavity
Transudate fluid accumulation due to liver cirrhosis, compression of portal vein due to destruction of liver architecture, venous blood entering liver is backed into microvasculature
Liver cirrhosis: cobblestone appearance for gross anatomy, see blue stained CT on histology
Pulmonary Edema
Fluid accumulation in the alveoli
See white frothy transudate when lungs are pressed, clear air spaces of alveoli have pink fluid in them
Left heart failure: left heart can’t pump out normal amount of blood with each contraction due to aortic/mitral valve disease or damage to cardiac muscles by infarction/infection
Blood backs up in pulmonary veins, increases hydrostatic pressure on thin walls of alveoli
Peripheral Edema
Gravity causes increased venous hydrostatic pressure by ankles
Due to standing/sitting all day with little activity, venous blood pools
Pitting Edema (cutaneous edema)
Accumulation of interstitial fluid in the extremities, leaves pit after pressing
Causes: kidney disease, thrombosis in vein, inflammation of a vein, mass obstruction of a vein from pregnancy, congestive heart failure in right heart causes backup of blood returning to the heart from the lower limbs
Decreased Oncotic Pressure
Decreased oncotic pressure in the capillary, causes edema
Causes-
1. Increased protein (albumin) loss: nephrotic syndrome leads to proteinuria, gastroenteropathy like diarrhea
- Decreased protein (albumin) synthesis: hepatic cirrhosis, malnutrition
- Excessive IV fluid during resuscitation from shock
Problem: anasarca
Anasarca
Decreased plasma oncotic pressure from low serum protein conc.
Malnutrition from Kwashiorkor, older baby stopped getting breastfed and switched to carb gruel diet
Altered Lymph Drainage
Amount of edema in the interstitial tissue exceeds ability of lymphatic System to drain it
Etiologies-
1. Primary: congenital, hereditary
- Secondary: infection/inflammation, surgical dissection (lymphadenectomy), chronic venous insufficiency
Obstruction/fibrosis from trauma, surgery, tumors, radiation therapy
Lymphedema
Clinical Features-
1. Usually unilateral, upper/lower limbs
- Made worse by prolonged dependency (gravity)
- Physical exam: increased limb diameter, sensory/ROM problems, edema may be pitting, brawny, or weeping
- Increased risk for infections
Can be from surgical trauma that destroys inguinal lymph node, axillary lymph node dissection due to breast cancer, lymphatic filariasis or elaphantiasis of scrotum
Hyperemia
Increased blood flow in an organ or tissue
Active hyperemia: increased blood flow in tissue/organ due to exercise or inflammation
Passive hyperemia (congestion): pooling of venous blood
Opening of precapillary sphincters in hypoxia, decreased pH, increased CO2, increased temperature, increased K+
Venous Congestion
Venous blood engorgement of an organ, increase in organ weight/size
Organ/tissue may appear cyanotic
Congestion often accompanies edema and may precede it
Pump failure or clogged pipes
Pump Failure
- Right side heart failure: congestion of spleen, liver, lower limbs
Enlarged right ventricle that looks like tennis shoe in X-ray
Cyanosis, dissension of jugular vein, hepatomegaly, splenomegaly
Hepatic congestion: nutmeg liver, expansion of hepatic sinuses
- Left side: pulmonary congestion
Cloudiness in chest X-ray, respiratory problems like dyspnea, orthopnea (can’t lie flat in bed)
Lungs appear blueish, acute congestion has edema filling in alveoli and alveolar Capillaries engorged with erythrocytes, chronic has widening of alveolar septa and alveolar macrophages with hemosiderin pigment (Prussian blue staining)
Clogged Pipes
Causes congestion
Venous thrombosis: blue leg, prevents venous drainage from lower limb, rare
Venous stasis: defective valves in large veins of the lower limb that lead to high venous pressure
5 steps to EBP
- Ask: a good question
- Acquire: get literature
- Appraise: see strengths/weakness of article
- Apply: make a decision based on what you’ve found and evaluated
- Adjust: evaluate the impact of the decision and start the process again
PICO
Patient, Problem, or Population: describe patient’s condition or disease state
Intervention: could be therapeutic, diagnostic, or etiologic
Comparison Intervention: other therapy, gold standard, or none
Outcome of interest: whether patient lives or dies, pop. has fewer strokes
Background vs. Foreground Questions
Background: general questions without comparisons
Foreground: specific questions that compare interventions
Cohort Study
Follow group of individuals forward through time to capture outcome
Why do it-
- Examine incidence
- Look at natural history of disease
- Assess temporality of an exposure/disease relation (when a RCT is not feasible)
Only way other than a RCT to ensure that exposure preceded disease
Disadvantages: costs a lot, not good for rare disease or if long latent periods, loss to follow up
