Robbins Chapter 3: Acute & Chronic Inflammation
Rubor, Tumor, Calor, Dolor, Functio laesa
(Redness, Swelling, Heat, Pain, Loss of function)
def. lasts minutes to days and characterized by exudation of fluid and plasma proteins and emigration of leukocytes, predominantly neutrophils.
1. Alterations in vascular caliber that lead to increased blood flow: vasodilation
2. Microvascular structural changes that allow exudation of plasma protens and leukocytes: increased permeability mediated by histamine, bradykinin, leukotrienes, substance P, endothelial retraction
exudate (s.g. > 1.012) vs. transudate (s.g. < 1.012)
3. Emigration of leukocytes: margination, rolling, adhesion, diapedesis, migration
neutrophils predominate (6-24 hours) and replaced by monocytes (24-48 hours)
E-selectin (endothelium) - rolling, adhesion [induced by IL-1 and TNF]
P-selectin (endothelium, platelets) - rolling [present in Weibel-Palade bodies]
L-selectin (leukocytes) - homing
ICAM (interacts with integrins LFA-1 on leukocytes) - adhesion, arrest, transmigration
VCAM (interacts with integrins on eos, monos, lymphs) - adhesion
PECAM-1 (CD31) - platelet-endothelial cell adhesion molecule
Chemotaxis - C5a, LTB4, IL-8
4. Leukocyte activation
Production of arachidonic acid metabolites
Modulation of leukocyte adhesion molecules
· Recognition and attachment via opsonization (Fc fragment of IgG, C3b, collectins)
· Engulfment via binding of the opsonized particle to the FcgR
· Killing or degradation via
- oxygen-dependent mechanisms using NADPH oxidase, myeloperoxidase (H2O2 + Cl- ® HOCl, destroys bacteria by halogenation)
- oxygen-independent mechanisms (bactericidal permeability increasing protein, lysozyme, lactoferrin, major basic protein, defensins)
After killing acid hydrolases in azurophil granules degrade bacteria within phagolysosomes
Leukocytes can also release products into the extracellular space (lysosomal enzymes, oxygen metabolites, arachadonic acid derivatives) during "regurgitation during feeding" (phagocytic vacuole open to outside transiently), "frustrated phagocytosis" (enzymes released but phagocytosis doesn't occur), "surface phagocytosis" (vacuoles are opened against a resistant surface) or exocytosis. After phagocytosis neutrophils may undergo Mac-1 mediated apoptosis.
One of Four Outcomes to Acute Inflammation:
1. Complete resolution
2. Abscess formation
3. Healing by connective tissue replacement (fibrosis)
4. Progression to chronic inflammation
Chemical Mediators of Inflammation
I. Vasoactive amines:
- Histamine (released by mast cell in respomse to physical injury, immune reactions, C3a, C5a, histamine-releasing protein, neuropeptides e.g. substance P, IL-1, IL-8)
- Serotonin (AKA 5-HT) released by platelets (on aggregation) and enterochromaffin cells
II. Plasma Proteases:
- Complement via classic (Ag-Ab mediated) or alternative (endotoxin-mediated) pathway ending in MAC (C5-C9) transmembrane attack complex
- C5a chemotactic factor - C3b and C3bi are opsonins
- controlled by protein inhibitors (C3 and C5 convertases, decay accelerating factor (DAF), factor I (cleaves C3b), C1 inhibitor, CD59)
III. Kinin System
Hageman factor (XII) binds to negatively charged surfaces:
Kininogens -(kallikreins)® kinins (vasoactive peptides) e.g. bradykinin
Kallikrein itself is a potent activatory of Hageman factor leading to autocatalytic activation
IV. Clotting System
Hageman factor (XII) stimulates intrinsic clotting cascade
Factor Xa is where intrinsic and extrinsic cascades converge (vascular permeability and leukocyte exudation)
Final step is creation of thrombin; (fibrinopeptides also vascular permeability and leukocyte exudation)
V. Arachidonic Acid Metabolites
AA is a 20-carbon polyunsaturated fatty acid that occurs as a membrane phospholipid and is released by phospholipase A2
AA is converted by lipoxygenase to LTA4, LTB4, LTC4, LTD4, LTE4
· LTB4 - chomataxis, neutrophil activation and adhesion, neutrophil generation of O2 free radicals and lysosomal enzyne relaese
· LTC4, LTD4, LTE4 - vasoconstriction, bronchospasm, vascular permeability
AA is converted by cyclooxygenase (mediated by COX1 and COX2 genes) to PGG2, PGH2, PGE2, PGD2, PGF2a, PGI2 (prostacyclin) and TXA2 (thromboxane)
· Prostaglandins - pain, fever, vasodilation
· Prostacyclin - vasodilator, platelet aggregation, potentiated permeability and chemotactic effects of other mediators
· Thromboxane - vasoconstrictor, platelet aggregation
Lipoxins are derived from AA via transcellular biosynthetic mechanisms (plt/neut interactions) - proinflammatory and anti-inflammatory actions: inhibit neutrophils but stimulate monocytes.
Aspirin and NSAIDS inhinit cyclooxygenase pathway (PG synthesis).
Glucocorticoids downregulate COX2.
Fish oil has linoleic acid and produces less potent leukotrienes (LTs).
VI. Platelet Activating Factor (PAF)
Derived from IgE-sensitized basophils.
Actions: plt aggregation, vasoconstriction, bronchoconstriction, adhesion, chemotaxis, degranulation and ox burst, synthesis of other mediators (eiconasoids)
VII. Cytokines and Chemokines
Effects are often redundant
Regulate lymphocytes: IL2, IL4, IL10, TGFb
Natural immunity: TNFa, IL1b, IFNa, IFNb, IL6
Activate inflammatory cells: IFNg, TNFa, TNFb, IL5, IL10, IL12
Hematopoiesis: IL3, IL7, c-kit ligand, GCSF, MCSF, GMCSF, stem cell factor
Control of acute phase response: TNFa and IL1
|C-X-C or a chemokines||Stimulate neutrophils||IL-8|
|C-C or b chemokines||Attract monos, eos, basos & lymphs||MCP1, MIP1a, RANTES|
|C or g chemokines||Lymphocytes||Lymphotactin|
|CX3C chemokines||Monos and T cells||Fractalkine|
VIII. Nitric Oxide
NO is a soluble gas which acts in a paracrine manner to induce cGMP in target cells
Produced by: endothelial cells, macrophages, neurons.
L arginine -(NO synthase, constitutive/induced)® NO
Actions: vasodilation, reduces platelet aggregation and adhesion, reduces leukocyte recruitment.
IX. Lysosomal Constituents of Leukocytes
Neutrophils have two majr types of granules:
azurophil (primary): larger, peroxidase-positive; MPO, lysozyme, defensins, acid hydrolase, neutral proteases (elastase, cathepsin G, proteinase 3, nonspec collagenases). Released into phagolysosome.
specific (secondary): smaller, peroxidase-negative - lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, alkaline phosphatase. Released extracellularly.
Acid proteases - degrade proteins at an acid pH within phagolysosome
Neutral proteases - degrade proteins extracellularly
Antiproteases - hold them in check, e.g. a1-antitrypsin (inhib neutrophil elastase), a2-macroglobulin
X. Oxygen-Derived Free Radicals
Superoxide (O2·), Hydrogen peroxide (H2O2), Hydroxyl radical (OH·)
Extracellular release can increases expression of chemokines (IL8), cytokines and endothelial-leukocyte adhesion molecules.
Antioxidants: ceruloplasmin, transferrin, superoxide dismutase, catalase, glutathione peroxidase.
Substance P: pain transmission, BP regulation, immune and endocrine cell secretion, increase vascular permeability
Leukocyte Adhesion Deficiency Type I
|Clinical: Impaired leukocyte adhesion and recurrent bacterial infections|
|Pathophysiology: Defect in integrin b2 chain (shared by LFA-1 and Mac-1): CD18|
Leukocyte Adhesion Deficiency Type II
|Clinical: Impaired leukocyte adhesion and recurrent bacterial infections (milder than LAD1)|
|Pathophysiology: Absence of sialyl-Lewis X, ligand for E-selectin, due to a defect in fucose metabolism|
Defects in Plasma Protease Activity
Paroxysmal Nocturnal Hemoglobinuria
Hereditary Angioneurotic Edema