D’YOUVILLE COLLEGE
PMD 604 - ANATOMY, PHYSIOLOGY, PATHOLOGY II
Lecture 4: Inflammation & fever
Robbins chapter 2, Hall chapter 16
1.
Background - Tissue Fluid Exchange:
• anatomy of microcirculation (H fig. 16 – 1, R fig. 2 – 2, ppts. 1 & 2)
- arterioles (muscular) branch to metarterioles (sparsely muscular), venules
drain microcirculation & lead to larger vessels of the venous system
- metarterioles may lead directly to venules via preferential channels (bypass
or shunt vessels)
- capillaries are smallest diameter vessels without muscle (except
precapillary sphincters, which may constrict to direct blood flow to preferential channel in
inactive tissues, or, in more active tissues, they may relax to permit maximal perfusion of
the capillaries; this process is called vasomotion
- permeability of capillaries varies widely from tissue to tissue; in 'tight
capillaries' permeability is very low (e.g., brain); in 'leaky capillaries' permeability is
very high to medium (e.g. liver, endocrine glands, kidney)
- most exchanges across the capillary wall occur via bulk flow (water +
solutes smaller than proteins) outward or inward
• pressures promoting fluid exchange (H fig. 16 – 5 & ppt. 3)
- filtration (outward) forces: blood hydrostatic P, tissue osmotic P
- absorption (inward) forces: plasma osmotic P, tissue hydrostatic P
- lymphatic drainage: removes filtration excess (H fig. 16 – 3 & ppt. 4)
- alteration of any of these principles (blood hydrostatic P, plasma osmotic
P, lymphatic drainage or relative permeability of microcirculatory vessel) may lead
to imbalance of tissue fluid exchange with the blood, e.g., at inflammation site (R fig.
2 – 2 & ppt. 5)
2.
Acute Inflammation:
• protective response:
- cardinal signs are: redness (rubor), warmth (calor), swelling (tumor), pain
(dolor) & altered function (functio laesa)
- acute inflammation facilitates removal or neutralization of noxious
stimulus (infection, traumatic stress, chemical stress, etc.) and prepares site for
healing
- response is delivered by a range of cellular & humoral components (R fig.
2 – 1 & ppt. 6)
• vascular changes: (ppt. 9)
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- p. 2 -
- vasodilation --> hyperemia (R fig. 2 – 2 & ppt. 5)
- increased permeability of post-capillary venules results from retraction of
endothelial cells, provoked by cytokines, e.g., tumor necrosis factor (TNF) or interleukin 1 (IL - 1); increases intercellular gaps between endothelial cells (ppt. 7)
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• edema (R fig. 2 – 3 & ppt. 8)
- types of edema: serous effusion (= transudate) is watery, resulting from
vasodilation without permeability change; with permeability increase, proteins and
cells are included in edema (= exudate)
- exudates: fibrinous (protein-rich), purulent or suppurative (contain white cells)
• cellular changes
- leukocyte recruitment & activation: margination, pavementing, emigration, ameboid
movement, chemotaxis & phagocytosis are included in white cell behavior facilitated by
signal molecules, e.g., cytokines (TNF, IL-1 & chemokines - from tissue macrophages) at
the inflammation site
- receptors expressed on endothelium of vessel adjacent to
inflammation site & receptors on activated leukocytes enable these interactions (R
figs. 2 – 4, R 2 – 6 & ppts. 10 & 11)
- types of defensive cells: tissue macrophages, mast cells, neutrophils
(=PMNs), monocytes, eosinophils, and lymphocytes (R fig. 2 – 1 & ppt. 12)
- PMNs predominate during early stages (6 - 24 hours) followed by
monocytes (24 - 48 hours) (R fig. 2 – 5c & ppt. 13)
- specific infections stimulate lymphocyte infiltration (viral infections) or
eosinophilic infiltration (parasitic infections or allergies)
• phagocytosis – (R fig. 2 – 7 & ppt. 14)
- opsonization: signal molecules (opsonins), e.g., complement components &
antibodies, facilitate recognition & engulfment
- microbicidal agents stored in lysosomes kill microbes, destroy bacterial
cell walls, produce acid &/or toxic conditions that debilitate microbes
- metabolically produced agents e.g., oxygen free radicals (ROS), halogen
derivatives & nitric oxide (NO) have powerful toxic effects on microbes
• chemical mediators of inflammation (R table 2 – 4, R fig. 2 – 14 & ppt. 15)
- products of cells (or platelets) at inflammation site or circulating in
inactive form in plasma bind to target cell receptors to induce their effects
- histamine (from mast cells & platelets) & serotonin (from platelets) increase
permeability of post capillary venules; blocked by antihistamines
- eicosanoids (derivatives of arachidonic acid from plasma membrane of
leukocytes & mast cells) are formed by cyclooxygenase (COX) pathways (e.g.,
prostaglandins & thromboxanes) or lipoxygenase pathway (leukotrienes) (R fig. 2 – 15 &
ppts. 16 & 17)
- COX pathways are blocked by steroids & NSAIDs (e.g.,
acetaminophen, ASA, ibuprofen)
- nitric oxide (produced by macrophages during inflammation) provokes
widespread effects promoting inflammatory response
- platelet-activating factor (from platelets, leukocytes, & endothelium)
activates platelets & leukocytes
- plasma-borne substances (formed in liver):
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- p. 4 -
- Hageman factor (R fig. 2 – 19, ppts. 18 & 19) causes formation of fibrin
(protein of clots), kinins (e.g., bradykinin) that activate pain receptors
- complement system  chemotaxis, opsonization, cell lysis (R fig. 2 – 18
& ppt. 20)
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- p. 5 -
• outcomes of inflammation: (R fig. 2 – 8, ppts. 21 & 22)
- edema - causes toxin dilution, swelling  pain (protective of affected part)
-provides proteins including antibodies (opsonins), bactericides,
antimicrobial agents & clotting factors
- phagocytic response - killing & degradation of infective agent; removal of
debris promoting healing
- result may be resolution (restoration of healthy normal tissue), fibrosis
(scarring, with loss of function) or chronic inflammation
- systemic effects:
- fever, lassitude, weakness, possibility of spread along lymphatics or to
bloodstream; provoked by pyrogens that stimulate prostaglandin release in hypothalamus
(site of body's temperature 'set point'); stimulates immune & phagocytic functions
and impairs microbial reproductive activity
- leukocytosis: neutrophilia (bacterial infections or tissue injury),
lymphocytosis (viral infections), or eosinophilia (allergies or parasitic infections)
- acute phase protein levels in the plasma are increased; these include
opsonizing proteins & fibrinogen (promotes increased erythrocyte sedimentation rate)
3.
Chronic Inflammation:
• basis for many diseases: conditions associated with chronic inflammation
are described with the suffix '-itis'
- failure of acute inflammation to dispatch injurious agent prolongs
inflammation for weeks, months or years; tissue damage may accrue from resistant
infections or autoimmunity or inability of a phagocyte to engulf a large injurious
agent
- lesion may involve a granuloma featuring a center of caseous necrosis
surrounded by enlarged macrophages, lymphocytes & fibrosis (R fig. 2 – 23 & ppts.
23 & 24)
- inflammatory cells, notably macrophages, (also lymphocytes & plasma cells)
dominate site, damaging functional tissue (R fig. 2 – 21 & ppt. 25)
- cells interact to produce cyclic stimulation of each other, prolonging the
condition (R fig. 2 – 22 & ppt. 26)
- healing processes may occur concurrently with continuing inflammatory
processes
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4.
- p. 6 -
Thermoregulation & Fever:
• maintenance of normal body temperature:
- temperature of body core, 37o C (98.6oF) (H fig. 73 – 1) - maintained by
negative feedback system for temperature regulation (ppt. 27): involves
thermoreceptors that signal hypothalamus
- input compared to ‘set point’ by hypothalamus; appropriate response
generated; signals sent to cerebral cortex (for behavioral response), to pituitary
(mediates thyroid response), and to various effectors (sweat glands, skin arterioles,
skeletal muscles)
- responses correct deviation from ‘set point’ (reverse direction of change =
negative feedback)
• hyperthermia
- excessive rise in core temperature (40.5o C or 105o F)
- accumulation of heat due to compromised sweating response or peripheral
vasodilation
- excessive heat production from overexertion at exercise
- hypothalamic dysfunction
- positive feedback (rise in metabolic rate produces more heat) may produce
further rise in core temperature culminating in heatstroke
• hypothermia
- drop in core temperature (< 35o C = mild hypothermia; < 32o C = severe
hypothermia)
- prolonged exposure to extreme cold; frostbite (= cell death due to heat loss)
- positive feedback – depressed metabolic rate (compromises heat
production), depressed respiratory & heart rate, impaired regulatory mechanisms
exacerbate decline in core temperature
- decline in metabolic demands (brain & heart) may outpace decline in
oxygen supply; results in prolonged survival despite moribund state
• pyresis (fever) – does not involve dysfunction of thermoregulation; instead,
the hypothalamic ‘set point’ is elevated by the action of pyrogens
- endogenous pyrogens (EPs)– substances released (largely by leukocytes)
at inflammation sites or in hypothalamus, e.g., tumor necrosis factor & interleukin-1
- EPs trigger elevation of set point through pathway involving
prostaglandins and other mediators (ppt. 28); thermoregulatory mechanisms then
proceed as normal responding to new set point
- antipyretics (e.g. ASA, acetaminophen) alleviate fever by returning set
point to normal via inhibition of PG synthesis (ppt. 29)
- cooling strategies provide relief & help alleviate fever, especially cold
cloths applied to nose and forehead (by cooling blood flow to brain)