Mediators of Inflammation😊

Mediators of Inflammation

Preformed Mediators

• Always present in the body.

1. Histamine and Serotonin:

• They are 1st hormones to be released during inflammation

Histamine:

• Richest source mast cells.

• Special stain for mast cells (and basophils):
• Toluidine Blue.

Serotonin:

• Richest source
• Enterochromaffin cells (intestine).

• Functions
• Vasodilation.
• Increased vascular permeability 
• (hallmark event).
• Bronchoconstriction 
• (involved in asthma).

2. Lysosomal Enzymes:

• Found in granules within lysosomes.

Granule Types and Contents:

Newly Synthesized Mediators

• Formed when infection occurs.

Nitric Oxide (NO):

• Function: 
• Vasodilation
• ⛔ Platelet aggregation 
• "Opens everything".

Platelet Activating Factor (PAF):

• Function: 
• Platelet aggregation
• Vasoconstriction
• "Activates everything", narrows things. Opposite to NO.

Chemokines:

Cytokines (Interleukins, TNF, Interferons):

• Cause Fever: 
• IL-1, IL-6, TNF-alpha

TNF-alpha:

• Causes fever.

• Causes decrease in appetite.

• Associated with pathogenesis of septic shock.

• Maintains granulomas in TB and Crohns Disease

• Mnemonic:
• Nananja thuni → ittal → Pani varum (fever),
• Food kazhikkan pattilla (↓ appetite),
• Kazhichal diarrhea avum (CD)
• Shock (septic shock) adikkum currentl thottaal

Interleukin Functions:

• TGF α →
• Menetriers (foveolar cell hyperplasia)

• TGF β →
• Most Fibrogenic

• IL12 and IFN γ →
• Granuloma formation in TB

IL-6:

Interferons:

• Mnemonic: Interfere while taking ABG and LFT

Arachidonic Acid Metabolites:

Eicosanoids

• Formed from
• arachidonic acid
• omega-6 fatty acid

• Examples:
• Prostaglandins
• Thromboxanes
• Leukotrienes
• Lipoxins etc.

• Origin:
• 20-carbon compound from phospholipids by phospholipase A2 & C.

COX (Cyclooxygenase) Pathway:

• Forms prostaglandins, Thromboxane A2 (TXA2).
• Sequence:
• PGG2 → PGH2 (makes the rest PGs).
• Mnemonic: alphabetical order G → H → D, E, F + I
• From G → H forms
• From H → I and DEF forms
• Compare I and TXA2
• I → Inhibit
• TXA → Aggregate (thromb → vasoconstriction)
• D → Dilate
• E → eeeee for pain
• F → Female → Carboprost
• Derivatives from PGH2:

Derivative	Function
PGD2	Vasodilation
PGE2	Pain (acts with Bradykinin)
PGF2 alpha	Acts on female reproductive system (e.g., Carboprost)

Derivative	Function
PGI2 (Prostacyclin)	• ↓↓ platelet aggregation • Cause vasodilation
TXA2 (Thromboxane A2)	• ↑↑ platelet aggregation • Cause vasoconstriction

• Pharmacology Integration:

Item	Function/Effect
COX-1	Gastroprotective
COX-2	Mediates inflammation
NSAIDs / Aspirin	⛔ both COX-1 & COX-2 ↳ risk of peptic ulcers
Selective COX-2 Inhibitors (e.g., Coxibs)	⛔only COX-2 ↳ ↓↓ GI side effects

LOX (Lipooxygenase) Pathway:

5-LOX Pathway:

• Forms leukotrienes
• LT B4: 
• Chemotaxis (part of LIC mnemonic).
• Chemokines:
• Bacteria () helps to form (Formyl methionine) LIC () for Tax (chemotax)
• LIC 4 (L B4) 85 (IL8, C5a) years
• LTC4, LTD4, LTE4:
• Act on lung leukotriene receptors
• bronchoconstriction (asthma)

• Leukotriene Receptor Antagonists (⇏ C, D, E)
  (e.g., Montelukast, Zafirlukast):
• ⛔ LTC4, LTD4, LTE4,

• Zileuton ⇏ 5 LOX
• stops entire pathway, incl. chemotaxis
• Not preferred for asthma alone.

12-LOX Pathway:

• Forms lipoxins.

• Lipoxins: 
• Anti-inflammatory action 

Complement System:

• Plasma proteins (partly newly synthesized, partly preformed).

Three Pathways:

End Result:

• Formation of MAC (Membrane Attack Complex).
• Composition: C5b to C9 
• Function:
• Bacterial lysis

• Man give money directly → 24 Lakh Mac

• Assistant give → 3 L Mac

• Class give → 1L mac
• To children from 5th std to 9th std (5b → 9)

• Mac koduth koduth theernnu poi (Mac deficiency) → avarkk Cap (capsulated) koduth

• Man (Mannose → C2, C4) Complement cheythillenkil (complement deficiency → autoimmuune)
• S = Swantham
• L = Lakshyam
• E = Ethire body Pravarthikkum

Complement Deficiencies:

• Most Common: 
• C2 deficiency.

• Early
• C1, C2, C4 deficiency
• A/w autoimmune disorder like SLE

• Late
• MAC deficiency
• Infections by capsulated organisms
• Disseminated Neisseria infection
• (meningococcus)

Hereditary Angioedema (HAE)

• Also: Quincke's Disease

• Autosomal dominant

• Bradykinin mediated

• NOT HISTAMINE MEDIATED

• Defect: C1 esterase inhibitor deficiency
• Leads to uncontrolled complement cascade
• C1 inhibitor normally controls C1 pathway.
• Deficiency → uncontrolled complement → episodic swelling (edema).

• Types based on C1 inhibitor:
• Type 1: Low C1 inhibitor protein concentration
• Type 2: Loss of C1 inhibitor function (quantity normal)
• Type 3: Normal C1 inhibitor → Factor 12?? (unknown defects)

• Presentation:
• Recurrent laryngeal edemas
• Colicky abdominal pain
• Recurrent angioedema
• Positive family history

• Evaluation:
• Screening: Low C4 level
• Specific: C1 inhibitor levels

• Treatment:
• Acute: Airway management
• IV C1-esterase inhibitor concentrate (C1-INH)
• Fresh frozen plasma (contains C1 inhibitor)
• DOC: Danazol
• Icatibant, Ecallantide
• Lanadelumab
• Ee kaatile Ee kallan Anade adyil
• Prophylaxis: Tranexamic acid, anabolic steroids
• Anabolic steroid Danazol may help.