ACUTE INFLAMMATION
A. Characteristics
1. Duration of inflammation minutes to a few days
2. Exudation of fluid and plasma proteins
3. Emigration of leukocytes, predominantly neutrophils
4. Response to many types of injury, including trauma, heat, cold, radiation, chemicals
5. Clinical signs are: heat (calor), swelling, redness (rubor), pain (dolor)
6. Lymphadenopathy (swollen glands) in draining lymph node areas may occur
7. Elevated levels of CRP and Interleukin 6 (IL6) associated with increased mortality risk [4]
B. Physiology
1. Hemodynamic changes with vasodilation
2. Increased vascular permeability, especially capillaries, arterioles
3. Antibodies and/or immune complexes can play a major role in initiation of inflammation
4. Exudation of leukocytes and production of antimicrobial agents
5. Neutrophils are major effector cells [12]
a. Production of highly reactive oxygen species (ROS) which have antimicrobial activity
b. Includes superoxide (O2-), hydrogen peroxide (H2O2), other peroxides
c. Toxic halogenated and nitrogenated compounds are produced
d. Result is excellent antimicrobial activity, but with collateral tissue damage
e. ROS also play a role in reperfusion injury
6. IgE plays major role in many cases of hypersensitivity
C. Hemodynamic Changes in Inflammation
1. Arteriolar microvascular dilatation
2. Venular constriction
3. Responses due to vasoactive compounds:
a. Histamine - potent vasodilator
b. Arachidonic Acid Metabolites: prostaglandins (PGs), thromboxanes, leukotrienes (LTs)
c. Nitric Oxide - vasodilation
4. Prostaglandins (PG) [9]
a. Various classes: vasodilators and vasoconstrictors, pro- and anti-inflammatory
b. Vascular dilatation primarily mediated by prostacyclin (PGI-2) and PGE2
c. Vasoconstriction mediated by other prostaglandins
d. Prostaglandin E2 (PGE2) is pro-inflammatory
e. PGD2 and PGF2a are anti-inflammatory
f. PGs are produced from arachidonic acid by several cyclooxygenases
g. Cyclooxygenases also called PG synthetases
h. At least two, and possibly three, PG synthetase isoenzymes exist
5. Nitric Oxide (NO) [3]
a. Potent relaxer of smooth muscle including blood vessel, esophageal, bronchial
b. Production of NO in brain inhibits alpha adrenergic tone and sympathetic outflow
c. Inhibits platelet aggregation
d. Inhibits smooth muscle proliferation
e. Inflammatory mediator (particularly in combination with reactive oxygen species, ROS)
f. In this regard, plays a role in host defense against microbes
g. Can react rapidly with free radicals, certain amino acids, transition metal ions
h. NO can also react with with ROS such as H2O2, superoxide
i. ROS reaction with NO can lead to formation of peroxynitrite (-NO2) which is toxic
j. In vascular space, NO is sacenvged by oxyhemoglobin forming methemoglobin and nitrate
k. Most absorbed NO is converted to nitrate and excreted in urine
6. Leukotrienes (LT) [2]
[Figure] "Leukotriene Synthesis"
a. LTs are primarily responsible for vasoconstriction and leukocyte exudation
b. They comprise the "slow reacting substance of anaphylaxis" or SRSA
c. SRSA is a combination of LT-C4, -D4 and -E4
7. Thromboxanes (TBX) are potent platelet activators and vasoconstrictors
8. Chemokines (see below)
a. Released by endothelium and fibroblasts
b. Potently leukocytes attractants
D. Vascular Permeability
1. Small and medium vessels, especially capillaries
2. Endothelial (pericyte) contraction allows "pore" formation in capillaries
3. Mediated by
a. Serotonin
b. Histamine
c. Bradykinin (BK)
d. Potentiated by vasodilators such as PGs and nitric oxide (see above)
e. Antibodies and/or immune complexes can also play a central role
4. Role of Kinins
a. Peptide mediators of acute and subacute inflammation
b. Generated by action of kallikreins (tissue and serum forms) - "contact-system"
c. Kallikreins act on high- and low-molecular weight kininogens
d. BK and kallidin (lysyl-BK) are produced
e. Cause vasodilation, vascular leak, pain and neurotransmitter release
f. Leads to local edema, blood pressure reduction, and pain
g. BK is degraded by angiotensin converting enzyme (ACE)
h. BK may be protective against development of left ventricular hypertrophy
i. Kinins also enhance cytokine, eicosanoid and nitric oxide (NO) release
j. Kinin type 1 receptors (B1) are inducible by inflammatory mediators such as IL1ß
k. Kinin type 2 recpetors (B2) are constitutively expressed
E. Leukocyte Exudation [10]
1. Leukocytes are part of the innate immune system with rapid responses to invaders [11]
a. The innate immune system is designed to react to a few, highly conserved, antigens
b. These antigens include lipopolysaccharide (LPS), teichoic acids, bacterial DNA, manins, and glucans
c. Various specific receptors have evolved to recognize these antigenic structures
d. Neutrophils and macrophages express many of these receptors
e. Activation of these cell types through these receptors leads to expression of costimulatory surface molecules, cytokine, and chemokine production
f. Some of the receptors are secreted and can stimulate the complement (C') system
2. Innate Immune System [11,16]
a. Mannan-binding lectin - initiates C' cascade
b. Macrophage mannose receptor
c. CD14 - one of the receptors for LPS, found on macrophages and B cells
d. Toll-like receptors (TLR) - various family members; TLR-4 involved in LPS binding
e. Activation of innate immunity leads to recruitment of adaptive immunity
f. Formation of Ab-Ag complexes is main way of activating classical C' pathway
g. Ag coupled to C' protein C3dg reduces threshold for B cell activation up to 10,000X
3. Leukocytes traverse vessel walls between endothelial cells in response to stimuli
a. Stimuli include leukotrienes (LTB4) and complement components (C5a > C3a >> C4a)
b. These may affect expression of cell adhesion molecules (CAMs)
c. Binding of CAMs to receptors is usually required for migration of effector cells
d. Inhibition of complement component formation can substantially block inflammation
e. Pexelizumab, a monoclonal antibody which binds C5 complement, showed no benefit in percutaneous coronary interventions [26]
4. Orderly Recruitment of White Blood Cells
a. Neutrophils (PMNs) enter first, then monocytes, then lymphocytes
b. Probable role of Cell Adhesion Molecules including LFA1, MAC1, VCAM-1, others
c. May also related to chemotactic factor production at specific site
d. These factors include potent chemotactic cytokines called chemokines
5. Leukocyte Migration [19]
a. Leukocytes migrate out of blood into tissue in particular fashions
b. Initially, adhesion of cells to blood vessel wall (endothelium) is required
c. Adhesion cascade includes: tethering, rolling, activation, firm adhesion, transmigration
d. Tethering requires selectins; these are proteins which bind to sugars (special lectins)
e. L-Selectin (CD62L) by leukocytes, P-Selectin by platelets, E-Selectin by endothelium
f. Rolling uses Integrins: Mac1 binds ICAM-1 (CD43), LFA-1 binds ICAM-1, and -2, and VLA4 binds to VCAM-1
g. Macrophages use Mac1, lymphocytes use LFA-1 and VLA4, eosinophils use VLA4
h. Transmigration across endothelium uses CD31 and other molecules
6. Chemokines
a. Two main types, alpha (CXC) and beta (CC) families
b. Families based on cysteine (C) residues
c. Alpha chemokines (including IL-8) act mainly on neutrophils
d. ß-chemokines on other cells
7. Roles of PMNs in Inflammation
a. Phagocytosis of bacteria, opsonized organisms
b. Includes killing of organisms with free radicals (superoxide) and halides (see below)
c. Tissue damage: oxidants, free radicals, proteases
d. Induction of distant effects: PMNs and monocytes make highly inflammatory IL1
F. Vasoactive Inflammatory Mediators
1. Histamine
a. Preformed vasoactive (arteriolar dilation) amines, mainly from mast cells
b. Release stimulated by IgE-R crosslinking and/or C3a/C5a binding to cells (see below)
2. Serotonin
a. Causes vasoconstriction is most vessels
b. Increases platelet aggregation (synergizes with collagen)
c. Direct constrictor effects on vascular smooth muscle
d. Preformed vasoactive (arteriolar dilation) amines, mainly from mast cells
e. Release stimulated by IgE-R crosslinking and/or C3a/C5a binding to cells
3. Bradykinin
a. Opposes effects of angiotensin II by inducing arteriolar vasodilatation and increasing vascular permeability
b. Kininogen converted to bradykinin (9-mer) through clotting cascade
c. Destroyed by ACE (Angiotensin converting enzyme; also called kininase)
d. Other effects include slowing of heart rate and smooth muscle contraction
4. Prostaglandins (PG)
a. Cyclooxygenase pathway (arachidonic acid), inhibited by NSAIDS, glucocorticoids
b. Prostacyclin: PG-I2 causes arteriolar dilatation along with PGE2
c. Thromboxanes: extremely potent, mediate vascular constrict and platelet aggregation
5. Leukotrienes (LT)
[Figure] "Leukotriene Synthesis"
a. Lipoxygenase pathway of arachidonate metabolism through 5-lipoxygenase (5-LO)
b. Synthesis blocked by glucocorticoids and 5-LO inhibitors
c. LT receptor blockers are also available
d. LTs include slow reacting substance of anaphylaxis (SRSA): LTE4
e. LTE4 causes vasoconstriction, bronchoconstriction, increased vascular permeability
6. Acetylated glycerol ether phosphocholine (AGEPC)
a. Originally called platelet activating factor (PAF)
b. PAF antagonists are being studied in sepsis and other inflammatory diseases
G. Complement (C') [5]
[Figure] "Complement Cascade"
1. The C' system consists of classical and alternative pathways
a. The classical pathway depends on antibodies (Abs) for activation
b. Abs may exist bound in solid phase to targets, or in circulating immune complexes (IC)
c. The classical pathway may be activated by either, provided the correct Fc is present
d. The alternative pathway can be activated directly by foreign cell membranes
2. Activation of the C' system by either pathway leads to C3a and C5a formation
a. C3a and C5a are potent activators of mast cells
b. C5a stimulates neutrophils as well
3. Inhibitors of C' Activation [22]
a. C1 Inhibitor - covalently binds C1r and C1s and blocks further activity
b. C4bp - accelerates decay of classical pathway C3 convertase (C4b2a)
c. Factor H (HF1) - accelerates decay of alternative pathway C3 convertase (C3bBb)
d. Factor I - proteolytically cleaves and inactivates C4b and C3b (cofactors needed)
e. Carboxypeptidase N - removes terminal arginine residues from C3a, C5a (inactivates)
f. Vitronectin (S Protein) - binds C5b-7 complex and prevents membrane insertion
g. SP-40 - modulates membrane attack complex formation
h. C' Receptor 1 (CR1, CD35) - dissociation of all C3 convertases, cofactor
i. Membrane Cofactor Protein - cofactor for Factor I mediated C3b and C4b cleavage
j. Decay Accelerating Factor (DAF) - accelerates decay of all C3 convertases
k. CD59 - inhibits lysis of bystander cells (C7 and C8 interactions)
l. Homologous Restriction Factor (HRF) - inhibits bystander lysis, C8 and C9 interactions
4. Disease and C' Inhibitors
a. Absence of C1 inhibitor leads to hereditary angioedema
b. Mutations in Factor H associated with familial hemolytic uremic syndrome (HUS) [22]
c. Mutations of membrane cofactor protein also associated with familial HUS [22]
d. Mutations in DAF or CD59 associated with Paroxysmal Nocturnal Hemoglobinuria (PNH)
e. Eculizumab is a recombinant antibody against complement protein C5
f. Blocks terminal complement activation by inhibiting C5 cleavage to C5a and C5b
g. Reduces intravascular hemolysis, hemoglobinuria, need for transfusion in PNH [24]
h. Pexelizumab, another Ab against C5, of no benefit in PCI (see above) [26]
5. Blockade of C' activation with soluble CR1 (sCD35) reduces tissue damage
H. Phagocytes and Microbial Oxidants [12,14]
1. Neutrophils and other phagocytes produce a variety of toxic oxidants
a. These molecules are called reactive oxygen species (ROS)
b. ROS include superoxide (O2-), hydrogen peroxide (H2O2), free radicals (OH·)
c. These ROS then form halide or nitrate derivatives
d. Hypochlorite (OCl-) and peroxynitrite (ONOO-) are highly toxic to microorganisms
e. However, these compounds also harm normal tissue, causing "collateral damage"
2. ROS are generated by four major enzymes in phagocytes
a. NADPH Oxidase
b. Superoxide Dismutase (SOD)
c. Nitric Oxide Synthetase (NOS)
d. Myeloperoxidase
e. Xanthine oxidase may play a major role in liver and intestine (but not heart)
f. Many other phagocyte oxidants are generated by noneyzmatic reactsion involving these ROS
3. NADPH Oxidase
a. Membrane-bound enzyme that catalyzes production of superoxide (O2-)
b. 2 O2 + NADPH --> 2 O2- + NADPH+ + H+
c. NADPH oxidase is dormant in resting phagocytes
d. NADPH oxidase is activated by a variety of inflammatory and bacterial stimuli
e. O2- is delivered to the external environment and into phagocytic vesicles
f. Chronic granulomatous disease (CGD) is due to defects in NADPH oxidase
g. Nitric oxide inhibits the function of NADPH oxidase [13]
4. Superoxide Dismutase (SOD)
a. Two forms of SOD: coper-zinc (cytoplasmic, SOD1) and manganese (mitochondrial)
b. Superoxide O2- is highly reactive and toxic
c. SOD catalyzes superoxide conversion to H2O2: 2 O2- + 2H+ --> O2 + H2O2
d. H2O2 is less toxic than than O2- but still highly reactive
e. H2O2 is normally detoxified by glutathione peroxidase (GPO) in higher organisms
f. Catalase can also detoxify H202, forming H20 and O2
5. Glutathione Peroxidase (GPO)
a. Catalyzes reduction of H2O2 to H20 and oxidation of glutationine
b. Also prevents oxidation of lipids to maintain biological membranes
c. Converts oxidized lipids (which are atherogenic) back to non-oxidized lipids
d. Strong inverse relationship between a patient's red blood cell GPO levels and risk of subsequent cardiovascular events [23]
6. Myeloperoxidase (MPO)
a. Heme enzyme which catalyzes oxidation of Cl-, Br-, I- (or SCN-) by hydrogen peroxide:
b. Cl- + H2O2 --> OCl- + H2O
c. OCl- is antimicrobial (but redundant systems are present)
d. MPO deficiency is common (~1/1000 persons), usually with mild or no symptoms
e. MPO is an abundant leukocyte enzyme elevated in fissured atherosclerotic plaques [21]
f. Plasma levels evaluated as predictor of any cardiovascular event in patients with angina
g. MPO levels at presentation also predicted risk of major cardiac events at 1 and 6 months
h. Risk ratios in the 2-4X range, even after correction for baseline troponin levels [21]
7. Major Nonenzymatic Reactions and ROS Products
a. Hydroxyl Radical (OH·)
b. Oxygenated Halogens (OCl-, others)
c. Singlet Oxygen (1O2)
d. Reactive Nitrogen Species
8. Hydroxyl Radical (OH·)
a. Generated by "Fenton Reaction": H2O2 + Fe2+ (Cu+) --> OH· + OH- + Fe3+ (Cu2+)
b. OH· can initiate a variety of free radical reactions involving biomolecules
c. OH· is therefore very destructive to biological systems
d. Fe3+ is reduced back to Fe2+ by ascorbic acid (vitamin C) and other antioxidants
9. Oxygenated Halogens
a. Initially, OCl- / HOCl are formed by MPO (major oxygenated halogen in body)
b. HOCl (hypochlorous acid) reacts with many amines to form chloramines
c. Lipophilic chloramines are highly toxic: chloramine (NH2Cl) and putrescine (H2N-C4H8NHCl)
d. Taurine chloramine (SO3=CH2-CH2-NHCl) is water soluble and nontoxic
e. HOCl can also react with amino acids to form chloramines and aldehydes
f. Aldehydes are highly reactive and toxic (used as fixatives in histology)
g. Oxygenated halogens are highly toxic to microbes, may be most important in neutrophils
10. Singlet Oxygen (1O2)
a. Oxygen normally has two unpaired electrons (diradical)
b. Singlet oxygen is much more reactive, in which these two electrons are paired
c. Singlet oxygen is produced in excess in patients with certain types of porphyria
d. Singlet oxygen is also produced by neutrophils: H2O2 + OCl- --> 1O2 + H2O + Cl-
e. Likely that singlet oxygen is responsible for some antimicrobial effects and tissue damage
11. Nitric Oxide Synthetase (NOS) [13]
a. At least three forms of the enzyme exist: 2 constitutive forms and one inducible
b. Constitutive NOS in brain (neuronal NOS or nNOS) and endothelial NOS (eNOS)
c. Inducible NOS is associated primarily with inflammation (iNOS)
d. Inducible form produced by phagocytes and other cells when stimulated
e. All NOS catalyze production of nitric oxide (NO) from arginine
f. Arginine + O2 + NADPH --> NO + citrulline + NADP+
g. NOS is highly complex, containing FAD, FMN, heme, and biopterin
h. Major role of NO in inflammation is conversion to peroxynitrite and other toxic metabolites
i. Note that NO is a weak free radical
j. Inhibition of iNOS can worsen tissue damage in some inflammatory settings [13]
k. Therefore, the physiological role of iNOS in inflammation is complex
12. Reactive Nitrogen Species
a. Formed by combination of NO with superoxide (O2-) or other ROS
b. A variety of species have been discovered including peroxynitrite (ONOO-)
c. Peroxynitrite can combine with carbon dioxide, HOCl or other molecules
d. Nitration of tyrosines in proteins leads to damage and dysregulation
13. Free-Radical Scavenger NXY-059 [25]
a. Reduces size of infarct in various animal stroke models and is neuroprotective
b. Administration within 6 hours in acute stroke reduced disability at 90 days
c. No effect on NIH Stroke Scale or Barthel index
I. Fever [4,20]
1. Mediated by exogenous and endogenous pyrogens
2. Central Nervous System (CNS) and Thermoregulation
a. Temperature regulation is primarily at the CNS level
b. Hypothalamus and limbic system outputs are key
c. Preoptic region, including medial and lateral aspects of preoptic area, is critical
d. The anterior hypothalamus and septum also play major roles
e. Outputs from these areas travel down through reticular formation and spinal cord
f. Thermoregulatory centers integrate inputs from skin thermosensors and core body areas
g. A physiological thermal set point exists in the preoptic area
h. This set point is developmentally determined and varies amongst individuals
i. Normal set point is ~37°C (98.6°F)
3. Major Exogenous Pyrogens
a. Gram Negative Lipopolysaccharide (Endotoxin)
b. Gram Positive Bacterial Molecules - lipoteichoic acids
c. Viruses
d. Fungi
e. Protozoa
f. Bacterial superantigens - toxic shock and other toxins
4. Major Pyrogenic Cytokines (Endogenous Pyrogens)
a. Interleukin 1 (IL1)
b. Interleukin 6 (IL6)
c. Tumor Necrosis Factor Alpha (TNFa)
d. Interferon Gamma (IFNg)
e. Prostaglandin E2 is likely the common pathway at hypothalamic level
f. IL6 is the major inducer of acute phase reactants
g. TNFa and IL1ß levels predict relapse in Crohn's (inflammatory bowel) Disease [6]
5. Fever Suppression [20]
a. Acetaminophen, aspirin, non-steroidal antiinflammatory drugs (NSAIDs) are mainstay
b. Primarily work by inhibition of prostaglanding E2 synthesis (mainly through COX2)
c. Aspirin and NSAIDs have peripheral antiinflammatory activities also
d. Acetaminophen only has central actions
J. Acute Phase Reactants (APR) [4,7]
1. Cytokines stimulate fever as well as regulate the synthesis of a variety of proteins
2. These proteins are called "acute phase" reactants or proteins (APR)
3. There are both positively and negatively regulated ACR
4. The erythrocyte sedimentation rate (ESR) is an indirect measure of APR
5. IL6 is the major stimulator of APR
a. IL1ß also plays a role
b. CRP (C-reactive protein) is the most common clinical marker for inflammation
c. IL6 directly stimulates CRP production, mainly from hepatocytes
d. Elevated CRP is strongly associated with atherosclerosis [17] and type 2 diabetes [18]
e. Elevated CRP and IL6 are associated with increased mortality in elderly [4]
6. Chronic expressin of APR likely contributes to cachexia [15]
7. The following APR levels increase with inflammation:
a. Fibrinogen
b. Plasminogen
c. Tissue plasminogen activator (TPA)
d. Plasminogen activator inhibitor 1 (PAI-1)
e. Urokinase
f. Protein S
g. Vitronectin
h. C-Reactive Protein (CRP)
i. Serum Amyloid A
j. Haptoglobin
k. Alpha1-Acid Glycoprotein
l. Fibronectin
m. Ceruloplasmin
n. Haptoglobin (moreso than hemopexin)
o. Ferritin
p. Complement Proteins C3, C4 and C9
q. Complement C1 Esterase Inhibitor
r. Complement C4b Binding Protein
s. Complement Factor B
t. Mannose binding protein (lectin)
u. Alpha1-antichymotrpsin
v. Pancreatic secretory trypsin inhibitor
w. Alpha1-Protease Inhibitor
x. Alpha2-Macroglobulin
y. Phospholipase A2
z. Pancreatic secretory trypsin inhibitor aa. Inter-alpha protease inhibitor
8. The following ARP levels decrease with inflammation:
a. Albumin
b. Transthyretin (Prealbumin)
c. Transferrin
d. Alpha2-HS Glycoprotein
e. Alpha-fetoprotein (AFP)
f. Thyroxine binding globulin
g. IGF-1
h. Clotting Factor XII
9. Role of APR [7]
a. Replaces normal set of homeostatic proteins
b. Resets equilibrium / homeostasis set point
c. Likely net effect to improve defensive and adaptive capabilities
d. Patterns of cytokine production and APR different with different stimuli
10. Elevated IL-6 and C-reactive protein levels are associated with mortality in elderly [8]
K. Summary of Acute Inflammatory Response
1. Vascular Leakage
a. Histamine
b. Kinins and substance P (pain)
c. Prostaglandins and Leukotrienes
d. Serotonin
2. Neutrophil Migration
a. Activation by C5a >> C3a
b. IL-8 and other chemokines
c. Eosinophilia may also occur
3. Fever Induction
a. Exogenous pyrogens stimulate PGs and various cytokines (endogenous pyrogens)
b. Necrotic tissue stimulates endogenous pyrogens
c. Endogenous pyrogens stimulate CNS preoptic center neurons
d. CNS outputs stimulate heat production by visceral organs in the body
e. Result is usually a fever
f. Increased shivering or very high levels of pyrogens may lead to hypothermia
4. Antibodies (if preformed or made locally) can potentiate these responses
5. Acute Tissue damage due to effector cell lysosomal / oxidative products
6. Induction of Acute Phase Reactants (ARP) as described above
HISTOPATHOLOGIC PATTERNS IN INFLAMMATION
A. Serous
1. Mild injury, with epithelial destruction
2. Examples: water blister, burns
3. Primarily fluid accumulation (transudate)
B. Fibrinous
1. Exudation of fluid rich in plasma proteins, containing fibrinogen
a. Fibrinogen converted to fibrin by thrombin
b. Cells are not involved in this process (humoral process)
2. Fibrin forms and serves as scaffolding for growth of connective tissue
3. Example: pericarditis
C. Pseudomembrane Formation
1. Formation of new pseudomembrane on top of original one
2. Similar to fibrous: covering of mucosal surface with fibrin, inflammatory cells, necrosis
3. Often, only the very top of the original membrane is hurt, but function is compromised
4. Examples a. Pseudomembranous colitis (C. difficele)
b. Diphtheria
D. Suppurative (Purulent)
1. Fluid is rich in neutrophils (dead) and target organism
2. Frequent with gram+ infections, especially Staphylococcus
3. Local collection of pus within tissue, organ etc, result is an abscess
4. Abscess formation often by gram negative organisms: E. coli, Klebsiella, Bacteroides ssp
5. Congenital Immunodeficiency Diseases
a. Associated with defects in anti-microbial activity
b. Chediak-Higashi Syndrome
c. Chronic Granulomatous Disease
d. Glucose 6-P Dehydrogenase (G6PD) Deficiency: Impaired H2O2 Production
6. Chediak-Higashi Syndrome
a. Large azurophilic granules not degranulated
b. Poor neutrophil locomation
c. Autosomal recessive gene
7. Chronic Granulomatous Disease (CGD) [12]
a. Defect in antimicrobial oxidants due to one of four distinct mutations
b. Most common (65% of CGD) is defect in 65K protein on chromosome Xp21
c. This is a mutation in one of the two subunits of cytochrome B (gp91 phox)
d. The other 35% of CGD are missing either the other subunit of cytochrome B or one of the two regulatory subunits; all of these forms are autosomal
8. Other Diseases with High Risk Suppurative Infections
a. Hypogammaglobulinemia
b. C3 and other complement deficiencies
c. Sickle Cell Disease
9. Sickle Cell Anemia
a. Patients "auto-splenectomize" due to infarction of spleen
b. Especially susceptible to encapsulated organisms
c. Increased risk of Salmonella infections
E. Ulcer
1. Shedding of inflamed tissue on surface of an organ
2. Crater which remains is referred to as an ulcer
3. Strict definition requires denuding of epithelia, causing an ulcer at the particular point
References
--------------------------------------------------------------------------------
1. Kahn R, Herwald H, Muller-Esterl W, et al. 2002. Lancet. 360(9332):535
2. Peters-Golden M and Henderson WR. 2007. NEJM. 357(18):1841
3. Griffiths MJ and Evans TW. 2005. NEJM. 353(25):2683
4. Stork S, Feelders RA, van den Beld AW, et al. 2006. Am J Med. 119(6):519
5. Hricik DE, Chung-Park M, Sedor JR. 1998. NEJM. 339(13):888
6. Schreiber S, Nikolaus S, Hampe J, et al. 1999. Lancet. 353(9151):459
7. Gabay C and Kushner I. 1999. NEJM. 340(6):448
8. Harris TB, Ferrucci L, Tracy RP, et al. 1999. Am J Med. 106(5):506
9. Willoughby DA, Moore AR, Colville-Nash PR. 2000. Lancet. 355(9204):646
10. Delves PJ and Roitt IM. 2000. NEJM. 343(1):37
11. Medzhitov R an d Janeway C Jr. 2000. NEJM. 343(5):338
12. Babior BM. 2000. Am J Med. 109(1):33
13. Kubes P and McCafferty DM. 2000. Am J Med. 109(2):150
14. Lefer DI and Granger DN. 2000. Am J Med. 109(4):315
15. Kotler DP. 2000. Ann Intern Med. 133(8):622
16. Walport MJ. 2001. NEJM. 344(15):1140
17. Ridker PM, Cushman M, Stampfer MJ, et al. 1997. NEJM. 336:973
18. Pradhan AD, Manson JE, Rifai N, et al. 2001. JAMA. 286(3):327
19. Westermann J, Engelhardt B, Hoffmann JC. 2001. Ann Intern Med. 135(4):279
20. Aronoff DM and Neilson EG. 2001. Am J Med. 111(4):304
21. Brennan ML, Penn MS, Van Lente F, et al. 2003. NEJM. 349(17):1595
22. Noris M, Brioschi S, Caprioli J, et al. 2003. Lancet. 362(9395):1542
23. Blankenberg S, Rupprecht HJ, Bickel C, et al. 2003. NEJM. 349(17):1605
24. Hillmen P, Hall C, Marsh JCW, et al. 2004. NEJM. 350(6):552
25. Lees KR, Zivin JA, Ashwood T, et al. 2006. NEJM. 354(6):588
26. APEX AMI Investigators. 2007. JAMA. 297(1):43
