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Acute Inflammation

Closely intertwined with process of Repair Fundamentally protective response, may be potentially harmful


  1. Circulating cells,                             
  2. Plasma,
  3. Blood vessels,                                
  4. Cellular & extra-cellular constituents of connective tissue

Acute & Chrome

A. Acute-

  1. Rapid onset (sec. - min.)                
  2. Short duration: lasts for min. → hrs. → day.


Exudation of fluid & PP (oedema) and extravasation of leukocytes (Neutrophils)


B. Chronic: -

  1. longer duration associated with presence of lymphocytes & macrophages
  2. Proliferation. of BVS, fibrosis, tissue necrosis
  3. Vascular & cellular responses of both acute/ chronic inflammation are mediated by - chemical mediators derived from plasma / cells 

Historical Milestone

  1. Celsus (3000 B.C.) – five cardinal features are -
  2. Rubor, Tumor,Calor, Dolor,Virchow - Functio laesa. Q
  3. Elie Metchnikoff → Phagocytosis Q
  4. Sir Thomas Lewis → Histamine Q
  5. John Hunter → inflammation not a disease but a non specific response. Q
  6. Julius Cohnheim → First used microscope to observe inflamed blood vessels. Q

Difference between Exudate and Transudate

Exudate Transudate
Inflammation Oedema Non Inflammation
permeability Hydrostatic Imbalance
Escape of fluids,   Ultra-filtrate of plasma
Contains Proteins, cells / no proteins (albumin)
Specific Gravity> 1.020    Specific Gravity < 1.012



Fig 1: The major local manifestations of acute inflammation, compared to normal.

Vascular changes are the hallmark of Acute Inflammation.
  1. Vascular Events
  2. Cellular events
    1. Vascular dilation and increased blood flow (causing erythema and warmth) , Q
    2. extravasation and deposition of plasma fluid and proteins (edema), and
    3. leukocyte emigration and accumulation in the site of injury.
  3. Stimuli for acute inflammation:
    1. Infections (bacterial, viral, parasitic) and microbial toxins
    2. Trauma (blunt, penetrating)
    3. Physical and chemical agents (thermal injury, radiation, chemicals)
    4. Tissue necrosis
    5. Foreign bodies (splinters, dirt, sutures)
    6. Immune reactions
D. Vascular changes:

  1. Formation of endothelial gaps in venules: Gaps due to endothelial contraction Q
    1. Most common Mechanism
    2. Only venules (20-60 m)
    3. Vasoactive mediators Q                        
    4. (Histamine, Bradykinin, Subst. P, Leukotrienes)
    5. Occurs rapidly                                
    6. Reversible   Immediate transient response
    7. Short lived (15 – 30 min)
  2. Gaps: Endothelial retraction, cytoskeletal reorganization
    1. Mostly venule: capillaries Subject: Cytokines (IL-l, TNF, IFN -?)
    2. Hypoxia & sublethal injury
    3. Reversible
    4. Delayed (after 4-6 hours)
    5. Long lived ( ≥ 24 hrs.)
  3. Direct Injury: Endothelial Cell necrosis & detachment Q
    1. Arterioles, capillaries, venules                    
    2. Toxins, burns, chemicals, Infections
    3. Stars early immediate                                 
    4. Sustained (several hours)
→ Immediate sustained response
  • Associated with platelet adhesion and thrombosis
  1. Increased transcytosis
    1. Venules      
    2. VEGF, Histamine  
    3. Vesciculo vascular organelle (close to I/C jn) "
  2. Leukocyte mediated injury
    1. Late response (Leukocytes adhere early)         
    2. Mostly venules, pulmonary & Glomerular Capillaries
    3. Release toxic O2 species → endothelial Injury
  3. Leakage from new Blood Vessels BVs: Leaky VEGF → causes angiogenesis also ↑ permeability
  1. Cellular EventsQ
    1. Adhesion and transmigration                     
    2. Chemotaxin            
    3. Phagocytosis
  1. Steps: Q
    1. Lumen: Margination  
    2. Rolling - transient adhesion
    3. Adhesion
      1. Transmigration across endothelium (diapedesis) Q
      2. Migration in interstitial tissue (to chemotactic stimulus)
  2. Stasis Q
    1. Margination    
    2. Rolling
    3. Firm adhesions (pebbles/marbles pavementing)
  1. Adhesion and transmigration
    1. Complementary adhesion molecules binding
    2. Chemical mediators
  2. Adhesion molecules:
    1. Selectins                                                                     
    2. Immunoglobulins - ICAM-l, VCAM-l
    3. Integrins - Heterodimeric glycoproteins a & ß chain)            
    4. CAM - 1 binds ß2 integrin LFA-l, MAC - 1
    5. VCAM- 1 binds ß1 integrin VLA4                                   
    6. Mucin like Glycoproteins
    7. D31
Fig 2: The complex process of leukocyte migration through blood vessels
Fig 3: The Cell adhesion Molecules
  1. Transmigration (pred. venules)
    1. Intercellular jns. - PECAM - 1/ CD 31
    2. Pierce the basement membrane by secreting collagenases
      a. 6-24 hrs. – Neutrophils
      b. 24-48 hrs. – Monocytes
  2. Because of
    1. Neutrophils. - short life (apoptosis after 24 - 48 hrs.) Q
    2. Pseudomonas: Neutrophils (2-4 days)
    3. Viral in infection: Lymphocytes (First to arrive)
    4. Hypersensitivity reactions: Eosinophils
  3. Chemotaxis:  Q
    1. Locomotion oriented along a chemical gradient.   
    2. Exogenous. - bacterial products
    3. Chemoattractants Endogenous                              
    4. Complement compo (C5a)
    5. Products of lipio-oxygenase pathway, Cytokines
  4. How does a leucocyte move?

Actin regulating proteins –  are - Q
  1. Filamin,      
  2. Gelsolin,     
  3. Profilin and            
  4. Calmodulin also interact.
  1. Steps In
    1. Leucocyte Activation
      1. Production of arachidonic acid metabolites
      2. Activation of phospholipase A2         
      3. Degranulation & secretion of lysosomal enzymes Q & activation of oxidative burst
      4. Secretion of cytokines which regulates inflammatory reaction
      5. Modulation of leukocyte adhesion molecules

Surface to receptors for leucocyte activation
  1. Toll like receptors (TLRs) activate leucocytes in response to different types and components of microbes.
    1. 10 TLRs identified till date
    2. TLR - ligand binding → production of microbicidal substances and cytokines in leucocytes.
  2. Seven transmembrane G coupled receptors Q
    1. Have 7 transmembrane a helical domain
    2. Ligands are - short acting peptides with N-formyl methionyl residue, chemokines, lipid, mediators-PAF, PGE, LTB4.
    3. Result in chemotaxis
  3. Receptors for cytokines like IFN-GAMMA
    Major macrophage activating cytokine
    Source of IFN-GAMMA- NK cells during innate immunity and antigen activated T cell (adaptive immunity) - Promote phagocytosis
  1. Recognition & attachment of particle to be ingested
  2. Engulfment - formation of phagocytic vacuole
  3. Killing or degradation
  1. Recognition & attachments:
    Leucocytes recognize microbes and dead cells by receptors
    1. Mannose receptor Q -bind mannose and fucose residues of glycoprotein in microbial cell wall
    2. Scavenger receptors Q - originally defined as molecules that bind modified LDL particles. Also bind microbes
    3. Mac 1 integrinsQ
Efficiency of phagocytosis increased by opsonization.

Opsonins –
Bind to specific receptors on leukocytes Receptors
- Fe fragment of IgG →Fc gamma R1
- C3b & C3bi →CR 1, 2, 3
- Plasma proteins:  
1. Mannose binding lectins →C1q
2. Fibrinogen  
3. Fibronectin →Integrins
4. C-Reactive proteins  

Neutrophils & macrophages: can recognize engulf bacteria & extraneous matter (in absence of opsonins)
  1. Engulfment:
    1. Pseudopods Q of phagocyte flow around the microbe to be engulfed Microbe enclosed in a phagosome
    2. Phagosome fuses with lysosome – phagolysosome Q
    3. Degranulation Q into phagolysosome and bacterial killing.
    4. Biochemical events of engulfment same as chemotaxis Killing
  2. Degradation
    1. Mainly: O2 dependent Mechanisms­
      1. Activation of NADPH oxidase
      2. HOCl: - Halogenation
      3. Peroxidation
    2. Lesser known mechanism is H2O2 - MPO - halide: - but it’s the most. efficient bactericidal system -effective. against fungi, viruses, protozoa, helminths
Defects In Leukocyte Function
  1. Defects in leukocyte adhesion:
    1. LAD 1: ß chain of CD11 /CD 18 integrins all deficient - repeated bacterial infection/impaired wound healing
    2. LAD 2: Absent Silalyl Lewis X (milder) (defective fucosyl transferase)
  2. Defects in Phagocytosis:
    1. Chediak Higashi Syndrome Q
      a. AR              
      b. Neutropenia
    2. Defective degranulation & delayed microbial killing
Neutrophils: Giant granules (in P/S)(aberrant organelle fusion), neutropenia
- Disorder in membrane associated protein which is involved in organelle membrane docking & fusion
- ↓ transfer of lysosomal enzymes
To phagocytic vacuoles: - ­­ ­infections
Melanocytes - Albinism
Cells of CNS - Nerve defects
Platelets - Bleeding disorders

Table: Clinical Examples of leukocyte – Induced injury
Acute Chronic
Acute respiratory distress syndrome Arthritis
Acute transplant rejection Asthma
Asthma Atherosclerosis
Glomerulonephritis Chronic lung disease
Reperfusion injury Chronic rejection
Septic shock  
Table: Defects in Leukocyte Functions
Disease Defect
i. Leukocyte adhesion deficiency 1 Beta chain of CD11 /CD18 integrins
ii. Leukocyte adhesion deficiency 2 Fucosyl transferase required for synthesis of silylated oligosaccharide (receptor for selectin)
iii. Chronic granulomatous disease Decreased oxidative burst
X-linked NADPH oxidase (membrane component)
Autosomal recessive NADPH oxidase (cytoplasmic components)
iv. Myeloperoxidase. Deficiency Absent MPO-H,O, system
v. Chediak-Higashi syndrome Protein involved in organelle membrane docking and fusion
1. Thermal injury, diabetes, malignancy, sepsis, immunodeficiencies Chemotaxis
2. Hemodialysis, diabetes mellitus Adhesion
3. Leukemia, anemia, sepsis, diabetes, neonates, malnutrition Phagocytosis and microbicidal activity

Defects of Microbicidal Activity:
Chronic granulomatous diseases: Q inherited defect in genes encoding several, components of NADPH oxidase (which generates superoxide)
  1. X linked: most common
  2. AR
Fig 4: Chemical mediators of inflammation. EC, endothelial cells.

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