Inflammation

Purpose is protective, physiologic response; begins within minutes to hours and lasts hours to days

Acute inflammation

Purpose is pathologic and progressively destructive; develops over days and may last weeks to years

Chronic inflammation

Primarily represents innate immunity; main cells are neutrophils and macrophages

Acute inflammation

Primarily represents adaptive immunity; main cells are macrophages, lymphocytes, and plasma cells

Chronic inflammation

Vascular changes include prominent vasodilation and increased vascular permeability

Acute inflammation

Vascular changes are less prominent, although angiogenesis may occur

Chronic inflammation

Usually self-limited injury, fibrosis generally mild, prominent local/systemic signs, typical outcome is healing

Acute inflammation

Progressive tissue destruction, fibrosis often severe, may have fewer obvious signs, can cause scar tissue, fibrosis, and organ or joint injury

Chronic inflammation

_________ factors contributing to acute inflammation include trauma, surgery, infection, caustic chemicals, and extreme heat or cold

Exogenous

________ factors contributing to acute inflammation include immune disease and ischemic injury

Endogenous

Four major goals are to neutralize or destroy the offending agent, localize damage to the smallest possible area, alert the body to injury, and prepare the tissue for healing

Acute inflammation

Tissue damage causes release of vasoactive and chemotactic mediators causing ________, increased vascular permeability, and neutrophil emigration

Vasodilation

What are the four key signs of inflammation?

Redness, heat, swelling, and pain

What produces redness and head during acute inflammation?

Increased local blood flow

What produces inflammatory swelling?

Increased vascular permeability

Endothelial gaps increase vascular permeability; vasodilation increases hydrostatic pressure; these changes produce net fluid movement out of the vessel and into tissue

Swelling

Contributes to inflammatory pain by directly activating nociceptors

Bradykinin

Contributes to inflammatory pain by sensitizing nociceptors, making chemical, mechanical, and thermal stimuli feel more painful

Prostaglandins

What causes loss of function during inflammation?

Pain, edema, and tissue injury

Vasodilation raises local blood volume and hydrostatic pressure, while endothelial gaps increase permeability. The net result during acute inflammation is movement of fluid ____ of the blood vessel

Out

Preformed in mast-cell granules; released after physical or microbial injury; causes vasodilation and increased vascular permeability; predominantly a vascular mediator

Histamine

Sources are brain, spinal cord, and inflammatory cells; binds neurokinin receptors; produces NO-mediated vasodilation; increases histamine, PGE2, macrophage cytokines, and chemotaxis

Substance P

Binds neurokinin receptors and produces NO-mediated vasodilation

Substance P

Directly activates nociceptors; stimulates phospholipase A2; causes vasodilation, pain, hyperalgesia, and neurogenic inflammation; promotes arachidonic acid formation

Bradykinin

________ promotes arachidonic acid formation

Bradykinin

Prostaglandins are produced through the ____ pathway

COX

Major effects are vasodilation, fever, pain sensitization, and local inflammation

Prostaglandins

Leukotrienes are produced through the ____ pathway

LOX

Major effects are neutrophil recruitment, bronchospasm, increased vascular permeability, allergic hyperreactivity, pro-inflammatory and bronchoconstrictive

Leukotrienes

Lipoxins are produced through the ____ pathway

LOX

Help resolve inflammation; stop further neutrophil recruitment; reduce leukotriene release; have an inverse functional relationship with leukotrienes at inflamed sites

Lipoxins

Which mediator directly generates pain?

Bradykinin

Which mediator predominantly sensitizes pain receptors?

Prostaglandins

Pro-inflammatory, increase neutrophil activity, permeability, bronchospasm, and hyperreactivity

Leukotrienes

Inflammation-resolving, stop neutrophil recruitment, reduce leukotriene release, and support noninflammatory clearance

Lipoxins

What dietary fatty acid supplies arachidonic acid?

Linoleic acid

Arachidonic acid is stored _______ within membrane phospholipids; it is not normally free floating in the cell

Esterified

Injury or inflammatory stimuli activate ________ ___, which releases arachidonic acid from membrane phospholipids. This is the rate-limiting step

Phospholipase A2

________ inhibit phospholipase A2 activation, broadly decreasing downstream products of both the COX and LOX pathways

Corticosteroids

What products arise from the COX pathway?

Thromboxane, Prostacyclin, Prostaglandins

What products arise from the LOX pathway?

Leukotrienes, Lipoxins

What products arise from CYP450 pathway?

EETs

NSAIDs inhibit ____, reducing prostaglandins, prostacyclin, and thromboxane to varying degrees

COX

These products may reduce some GI and platelet effects, but can increase thrombotic concern

COX-2 selective

Enzyme associated with leukotriene synthesis

5-LOX

Enzyme associated with lipoxin synthesis

12-LOX

Inflammatory effects include neutrophil chemotaxis, aggregation, and transmigration; bronchospasm; increased vascular permeability; hyperreactivity in asthma, allergy, and hypersensitivity

Leukotrienes

Stop neutrophil recruitment, reduce leukotriene release, promote macrophage phagocytosis of neutrophils without pro-inflammatory cytokine secretion, more activity generally corresponds to less leukotriene activity at the site

Lipoxins

Constitutively expressed; “housekeeping”

COX-1

Induced by inflammation but constitutive in select tissues; associated with inflammation, pain, and fever

COX-2

Maintains GI blood flow and mucosal proliferation

COX-1

Less dominant in routine GI protection

COX-2

Maintains renal blood flow and function

COX-1

Contributes to renal adaptation during stress

COX-2

Platelets primarily use ________ to produce TxAs

COX-1

Contributes to vascular homeostasis and PGI2

COX-1

An important source of endothelial PGI2

COX-2

Additional physiologic roles include bone deposition, ovulation, placentation, and labor

COX-2

Source is platelets; coupled to Gq

Thromboxane

Source is vascular endothelium; Gs coupled

Prostacyclin

Primary effect is vasoconstriction, increased platelet adhesion/aggregation, and a prothrombotic effect

Thromboxane

Primary effect is vasodilation, decreased platelet aggregation, and an antithrombotic effect

Prostacyclin

Prostacyclin is the ________ _______ of thromboxane. Their balance helps regulate vascular tone and platelet aggregation

Physiologic antagonist

Why do platelets primarily make thromboxane?

Contains thromboxane synthase

Why does vascular endothelium make prostacyclin?

Contains prostacyclin synthase

Why can selective COX-2 inhibition increase cardiovascular thrombosis?

Decreases endothelial PGI2 but platelet TxA2 remains preserved

Nonselective COX inhibitors inhibit protective ________ prostaglandins, decreasing GI blood flow and mucosal protection

COX-1

Common prostaglandin precursor; local tissue isomerases determine fate

PGH2

These have short half-lives and therefore primarily exert autocrine and paracrine effects near their site of synthesis

Prostaglandins

PGE receptor; Major effect is pain

EP1

PGE receptor; Major effect is vasodilation

EP2

PGE receptor; Major effect is bronchoconstriction

EP3

PGE receptor; Major effect is GI protection

EP4

What are the major physiologic effects of prostaglandins in pain?

Sensitize nociceptors

What are the major physiologic effects of prostaglandins in fever?

Hypothalamic PGE2 raises temperature regulation

What are the major physiologic effects of prostaglandins in inflammation?

Increase blood flow and leukocyte infiltration

What is the major role of prostaglandins in the GI tract?

PGE2-related mucosal protection

What is the major role of prostaglandins in the kidney?

Help maintain renal blood flow

What is the major role of prostaglandins in the uterus?

Promote contraction

What is the major role of prostaglandins in the fetus?

Maintain ductus arteriosus

What is the major role of prostaglandins in the eye?

Increase aqueous humor outflow

Most common arthritis; degenerative and inflammatory join disease; usually asymmetric or unilateral; common in hands, hips, knees, and spine; “wear and tear” pattern, especially in weight-bearing joints

Osteoarthritis

Stimuli and risk factors increase IL-1beta, TNF, and IL-6 which increase matrix metalloproteases

Osteoarthritis

In osteoarthritis, __________ ________ degrade cartilage proteins and matrix while inhibiting collagen and matrix production; the result is cartilage loss, joint-space narrowing, and progressive structural damage

Matrix metalloproteinases

Risk factors are increasing age, female sex, obesity (through mechanical load and adipose inflammatory proteins), previous joint injury, repetitive occupational stress, genetics or bone deformity, and diabetes/gout/rheumatoid arthritis

Osteoarthritis

Treatment primarily controls symptoms and pain with acetaminophen, NSAIDs or COX-2 inhibitors, intra-articular corticosteroids, topical counterirritants, SNRI analgesics, and opioid analgesics

Osteoarthritis

Osteoarthritis is usually asymmetric or ________

Unilateral

Most common systemic inflammatory disease; chronic, autoimmune, and systemic; symmetric or bilateral joint involvement; inflamed/swollen joints and bony erosions; other organ systems may be affected

Rheumatoid arthritis

Key findings are bony erosions, firm subcutaneous nodules, rheumatoid factor in serum

Rheumatoid arthritis

Involves autoimmune recognition of normal joint proteins leading to T-cell activation and plasma-cell production of autoantibodies

Rheumatoid arthritis

What are the key three cytokines involved in rheumatoid arthritis?

TNF-alpha, IL-1beta, IL-6

Increased RANKL is associated with ________ _______

Rheumatoid arthritis

Increased _________ activity in rheumatoid arthritis increases osteoclast activity and causes bony erosions

RANKL

In rheumatoid arthritis, increased synovial _____ and PGE2 contribute to swelling and inflammatory tissue changes

COX-2

Used in rheumatoid arthritis for symptom control; seldom adequate alone

NSAIDs

Used in rheumatoid arthritis short-term or to bridge anti-inflammatory therapy

Corticosteroids

Used in rheumatoid arthritis to modify disease and slow structural progression

DMARDs

Family of zinc-dependent enzymes that degrade components of the extracellular matrix, including collagen and proteoglycans; production and activation stimulated by pro-inflammatory cytokines; high in both osteoarthritis and rheumatoid arthritis

Matrix metalloproteinases

Inflammatory, autoimmune, multisystem disease; highly variable course and prognosis; constitutional manifestations may include fatigue, fever, anorexia, and weight loss

Lupus

Manifestations include arthralgia, myalgia, arthritis, and intermittent polyarthritis; skin/mucosa, synovium, serosa, kidneys, CNS, lungs, heart, and hematopoietic system may be involved

Lupus