Pathology

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Pathology (Dr. Rebosa) acute and chronic inflammation…part 1

Inflammation
- complex reaction to injurious agents (microbes, damaged and necrotic cells) refers to leukocyte/WBC.
- Consists of vascular response (vascular, leaks to extravascular space; unique feature leading to
accumulation of fluid and wbc in extravascular space), migration and activation of wbc and systemic
reactions.
- Protective response, goal of which is to red organism of initial cause (toxins and microbes) and
consequences (necrotic cells and tissue) of injury.
- Serves to destroy, dilute, or wall off injurious agents and trigger series of events that try to heal and
reconstitute damaged tissue.
- Mechanisms to get rid of injurious agents, includes entrapment and phagocytosis of offending agents.
Absence of inflammation
- Would let infections go unchecked and never heal
- Might remain permanent lesions though inflammation and repa0ir maybe potentially harmful
- Underlie common chronic disease (rheumatoid arthritis, atherosclerosis, lung fibrosis and
hypersensitivity)
- Repair by fibrosis leads to distinguished scars or fibrous bands causing intestinal obstruction or limit
mobility of joints
Anti-inflammatory agents
- Significant in controlling the harmful sequelae of inflammation but not interfere with its beneficial
effects
2 main component of inflammation
a. Vascular
b. Cellular
Tissue and cells involved includes
a. Fluids and plasma proteins, neutrophils, monocytes
b. Cellular – mast cells, fibroblast
Acute inflammation
- Rapid in onset
- Relatively of short duration
- Main characteristics: exudates of fluid and plasma proteins (edema)
- Emigration of leukocytes (predominantly neutrophil)
- Rapid response to injurious agents that serves to deliver mediators of host defenses wbc and plasma
components.
3 major components of acute inflammation
1. Vascular caliber alterations (increase blood flow)
2. Structureal change in microvasculature (permit plasma proteins and wbc to leave circulation)
3. Emigration to site of injury
Exudates – escape of fluid, proteins and blood cells from vessels to interstitial tissue and body cavity
Exudate
- Anti-inflammatory extravascular fluid
- High protein
- Cellular debris
- Specific gravity >1.020
Transudate
- Low protein
- <1.020
- Ultrafiltrate of blood plasma resulting from osmotic/hydrostatic pressure imbalance
Edema
- Excess of fluid in interstitial or serous cavity (exudates and transudate)
Pus
- Purulent exudates (inflammatory exudates filled with wbc, dead cells cell debris, microbes)
Stimuli for acute inflammation
1. Infection ( bacterial, viral, parasite, toxin)
2. Trauma (blunt and penetrating)
3. Physical and chemical (thermal injury/frostbite irradiation, environmental chemicals)
4. Tissue necrosis
5. Foreign bodies (splinter, dirt, sutures)
6. Immune response (hypersensitivity reaction)
Characteristic reaction
Vascular change
A. Change in the vascular flow and caliber
1. Vasodilation
a. Earliest manifestation
b. Outpouring of protein rich fluid into the extravascular tissue, loss of fluid results in red
cell conc., increase blood viscosity, stasis, wbc accumulation and margination
2. Vascular leakage (permeability)
a. Hallmark of acute inflammation
b. Escape of exudates into extravascular tissue
c. Loss of protein from plasma, decrease intravascular orsmotic pressure of interstitial
fluid, increase hydrostatic pressure in blood.
B. Mechanism responsible to permeability
1. Contraction of endothelial cell resulting in increase in interendothelial space
a. Most common mechanism of vascular leakage (histamine, bradykinin, leukotrienes,
neuropeptide, substance P)
b. Occurs rapidly after exposure to mediator and is reversible and short lived
c. Immediate transient response
2. Delayed prolonged leakage
a. Begins after a delay of 2-12 hrs, last for several hours and days
b. Leakage us caused by mild to moderate thermal injury, x-ray, UV, bacterial toxin
c. Late-appearing sunburn is a delayed reaction
3. Direct endothelial injury resulting to endothelial cell necrosis and detachment
a. Usually encountered on direct damage to endothelium ensure injury (burns and toxin)
b. Leakage starts immediately after injury and sustained at high level until damage vessels
are thrombosed or repaired (immediate sustained response)
4. Leukocyte-mediated endothelial injury
a. Wbc adhere to endothelium and activated in the process, releasing toxic O2 species and
proteolytic enzymes causing endothelial injury or detachment resulting in increase
permeability
5. Increase transport of fluid and proteins (transcytosis)
a. Through the endothelial cells
b. Involve channels consisting of clustered of interconnected, uncoated vesicles and
vacuoles
Cellular events (WBC)
A. Extravascular and phagocytosis
a. Critical function of inflammation is the delivery of wbc in the site of injury and its activation
for their function in the host defense
b. Wbc ingest offending agents, kill bacteria, microbes and rid of necrotic tissue and foreing
substances
c. Wbc may also induce tissue damage and in prolonged inflammation it can destroy normal
tissue
Sequence of evetns of migration
- Lumen, margination, adhesion to endothelium in inflammation, rolling , vascular endothelium is
activated permitting wbc to exit from the blood vessels
- Transmigration across the endothelium (diapedesis)
- Migration in interstitial tissue toward a chemotactic stimulus

I. Wbc adhesion and transmigration
- Regulated largely by binding of complementary adhesion molecules on the wbc and endothelial surface
and chemical mediators chemoattractants and cytokines
- Adhesion receptor: selectins, immunoglobulins, integrins, mucin like glycoproteins
o Selectins
 E selectin – along endothelium
 P selectin – endothelium and platelet
o Immunoglobulin
 ICAM – intracellular adhesion molecules
 VCAM – vascular cell adhesion molecules
 Both serve as ligands for intergrins found on wbc, also in endothelium
o Mucin like glycoproteins
 Heparin sulfate serve as ligands for wbc adhesion molecules (CD44) found in
extravascular matrix cell curface (at extravascular space)
o Integrins
 Binds to ligands
- Induction of adhesion molecules on endothelial cells
o Mediators include histamine, thrombin, PAF, stimulates redistribution of P-selectins from normal
intracellular stores in granules (Weibel-Palades bodies)
o Signals histamine, thrombin = bodies forms selectins
o Cytokines induction of endothelial adhesion molecules by IL-1, TNF
o Wbc adhere to B1 integrins and CD 44 once in extravascular area
- Clinical genetic deficiency in wbc adhesion proteins
o Impaired wbc adhesion
o Recurrent bacterial infection
o Wbc adhesion deficiency type 1 (LAD 1) –B2 chain defective synthesis by MAC 1 gene
- In most acute inflammation, neutron predominates in the first 6-24 hours then replaced by monocyte in
24-48 hours
o Neutron are more numerous in the blood
o Responds rapidly to chemokines
o Attached firmly to adhesion molecules that rapidly induced on endothelial cells such as P and E
selectins
o After entering tissue, neutro are short lived
o Except in pseudomonas infection which can be over 2-4days
o Viral infection (lympho)
o Hypersensitivity (eosin)
II. Chemotaxis
- Wbc migrate to site of injury
- Locomotions oriented along a chemical gradient
- Wbc varied in rate of response
- Endo and exogenous
Sensing chemotactic agents and induced directed cell movements:
- All chemotactic agents mentioned bind to specific 7 transmembrane G protein coupled receptros on the
surface of WBC
- Signals initiated form these receptor result in recruitment
- Wbc move by extending filopodia
- Filamin, gelsolin, profiling, calmodulin for contraction

III. WBC activation
- Microbes, necrotic cell products, antigen-antibody complex, cytokines induce wbc response leukocyte
defense function
- Functional response
o Produce arachidonic acid
o Degranulation and secretion of lysosomal enzymes and activation of the oxidative burst
o Secretion of cytokines (amplify)
o Modulation of wbc adhesion molecules
o Wbc surface receptors involved in theor activation (toll like receptor) – activate wbc in response
to different types and components of microbes, play essential roles in cellylar response to
bacterial lipopolysaccharides (LPS) endotoxin, proteoglycans, unmethylated CpG, nucleotides
(all found in bacteria), double stranded RNA (viral), dictates whether the enemy is pathogenic
Phagocytes express receptors in cytokines produced during immune response
- Interferon Gamma (most impt and major macrophage activating cytokines) secreted by NK cells during
innate natural response and by antigen activated T cells during adaptive immune response
- Opsonins
o Promote phagocytosis and deliver signals that active phagocyte
o Opsonization
 Coating a particle such as a microbe for phagocyte
 IgG Ab – most efficient opsonizing particle (specific opsonins) and recognized by FcY
receptor
IV. Phagocytosis
Steps (1. recognition and attachment of particle to be ingested by neutrophil, opsonization, 2.
Engulfment, vacuoles, 3. Killing, degranulation digestion with ROS, NO, and enzymes)

V. Release of WBC (products and WBC induce tissue injury)
o During activation and phagocytosis WBC release microbicidal infection phagolysosomes space and
extracellular space
o Lysosomal enzymes – most impt substances in neutron and macrophage presents
o Frustrated phagocytosis – there is a release of granules, potentially harmful, but the microbe was
not yet ingested.
VI. Defects in wbc function
o Phagolysosomes (chediak-higashi)
o Leukocyte adhesion ( LAN 1)
o Bone marrow depression
i. Most frequent cause of wbc defect leading to reduced production of wbc
ii. Caused by cancer and marrow space compromised by metastasis
iii. Resident cell in tissue serving transport function in acute infection
iv. Mast cell respond to immune reaction

Termination of acute inflammatory response
- Acute needs to be minimal
- Mediated have short life, degraded after their release, produced in quick bursts only as long as the
stimulus persists.
- Process also triggers stop signals serve to actively terminate the reaction which includes
o Switch in the production of pro inflammatory leukotrienes to anti inflammatory lipoxins from
arachidonic acid
o Liberation of anti inflammatory cytokines transforming TGF-B from macrophage
o Neural impulse (cholinergic discharge that inhibit TNF production in macrophage in chronic
inflammation
Mediators if inflammation
- Originates from plasma cells
Cell derived – normally sequestered in intracellular granules and can be reapidly secreted by granules exocytosis
(histamines in mast cells granules) or synthesis de novo (prostaglandins, cytokines) in response to a stimuli
- Major cell types that produce mediators of acute inflammation are platelets, neutrophil, monocyte,
mast cell and mesechymal cells (endothelium, smooth muscle, fibroblast)
Plasma derived
- In liver, in inactive precursor in circulation
o Active mediators are produced in stimuli (burn, toxin, microbial products, trauma, complement,
microbial, kinin, coagulated)
o One mediator can signal to release another mediator effect
o Mediator varies in various cell types target
o Once activated and release in cells , it is short lived
Chemical mediator of inflammation
- Vasoactive amine ( histamine, serotonin)
- Plasma protein ( complememtn, kinin, clotting factors)
- Arachidonic acid
- Platelet activiating factor
- Cyto/chemokines
- Nitric oxide
- Lysosome constituents
- ROS
- neuropeptides




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