Lecture 8: Inflammation and Mediators II

Sunburns

Cause Keratinocyte damage and release of IL-1

IL-1 increase leads to hypothalamic induction to raise body temperature

Immediate mediators of accute inflammation

Histamine, Bradykinin, Complement

Delayed lipid mediators of complement

Prostaglandin, leukotrienes, thrombaxane’s

Cytokines and eicosanoids

Cytokines tell cells what to do but eicosanoids produce many immediate physiologic manifestations of inflammation

AA Cascade

Fast Acting lipid network

Start as Arachidonic Acid

Responds to physical and chemical stresses (injury, pathogen, allergens)

Phospholipase A2 (PLA1) cleaves AA from cell membranes resulting in its release

2 pathways of AA

Lipoxygenase to Leukotriene

Or

Cyclooxygenase to prostaglandins and thromboxane’s

Corticosteroids and AA

Corticosteroids block PLA2 indirectly through annexin-1. They act upstream suppressing multiple inflammatory mediator families.

Lipoxygenase to Leukotrienes

Made by the breakdown of fatty acids like AA

Signals immune system to create an inflammatory response when triggered by allergens, cold air, or exercise.

LTB4

Drives inflammation and neutrophil recruitment

LTC4, LTD4, LTE4

Cysteinyl leukotrienes that constrict airways, increase mucous production, and increase vascular permeability. Types I hypersensitivity.

Increase in LTAs

results in restriction of bronchiole smooth muscle, airway narrowing, mucus buildup, and hyper responsiveness in asthma. Also leads to nasal polyps, congestion, allergies, and post nasal drop

COX to prostaglandins and thromboxanes

Converts AA into prostaglandin H2 (PGH2).

PGH2

Common precursor for prostaglandins, prostacyclin, thromboxane’s. Both catalyze the same reaction but differ in expression patterns.

COX-1

Housekeeping Enzyme

Expressed continuously in most tissue under normal circumstances

Maintains physiological homeostasis through production of protective prostaglandins.

Key functions of COX-1

Gastric protection: stimulates mucus and bicarbonate production, maintains mucosal blood flow

Platelet function: generates thromboxane A2 (TXA2) promoting platelet aggregation and hemostasis

Renal perfusion: helps regulate the kidney blood flow, particularly during stress.

Inhibition of COX1

Contributes to many NSAID adverse effects including gastric ulceration, GI bleeding, and renal toxicity

COX2

Inducible Inflammatory enzyme

Basally expressed at low levels in most tissue

Induced by the Big 3 and LPS/TLR signaling —→ activates NFkB

Generates large amounts of prostaglandins at sites of inflammation

Key functions of COX2

Promotes vasodilation

increases vascular permeability

Sensitizes pain receptors (hyperalgesia)

Contributes to fever through PGE2 production in the hypothalamus

Alternative functions of COX2

Plays a role in wound healing, vascular biology, and renal function

Traditional NSAIDs

Inhibit both COX1 and COX2 reducing inflammation but increasing GI toxicity risk

Selective Cox 2 inhibitors

Were developed to preserve COX1 mediated gastric problems while suppressing inflammatory prostaglandins

NFkB and COX2

NFkB drives COX2 transcription. COX serves as a key molecule link between innate immune activation and the cardinal signs of inflammation like pain, heat, swelling, redness.

PGE2

Fever

Vasodilation

Pain sensitization

Why NSAIDs reduce fever and pain

PGI2 (prostacyclin)

Vasodilation, inhibits platelet aggregation, endothelial protection.

PGE2 and PGI2

Synergize with the big 3 for hyperalgesia and drive hypothalamic fever axis via EP3 receptor

TXA2

Vasoconstriction, platelet aggregation

Role in thrombosis and aspirin therapy

Linking coagulation to immune response (immunothrombosis)

Lipid mediator class switch

Temporal shift as acute inflammation peaks, how inflammation knows when to stop.

Early inflammation

Large amounts of PGE2 and PGD2. Amplifies inflammation by promoting vasodilation, vascular permeability, pain and fever.

Increasing PGE2 and PGD2

Alter gene expression acting as molecular countdown timer.

Suppresses neutrophil recruitment and redirects AA metabolism away from proinflammatory mediators towards pro-resolving mediators (SPMs)

Enzyme Shunting LOX

As inflammation peaks PGE2 and PGD2 trigger a switch in lipid production, this is called enzymes shunting. It decreases LOX5 (dec. leukotrienes) and increases LOX 15 (inc. lipoxin, a SPM precursor)

Results of LOX shuntin

Stops further neutrophil recruitment

Dampens inflammatory signaling

Promotes macrophage mediated clearance of debris and apoptotic cells

Initiates tissue repair and restoration of homeostasis

Specialized Pro-resolving mediator examples

Lipoxins, Resolvins, Protectins, Maresins

Specialized Pro-resolving mediator results

Stop further neutrophil recruitment

Reduce inflammatory cytokine production

Enhance macrophage clearance of apoptotic cells

Promote removal of microbes and tissue debris

Stimulate tissue repair and regeneration

Restore normal tissue homeostasis

Lipoxin

LXA4 + LXB4

AA derived

Produced through LOX 15

Limit neutrophil recruitment and activation

Resolvins

Derived from EPA and DHA

Protectins

Derived from DHA

Maresins

Derives from DHA produced by macrophages

ALX/FPR2 (receptors)

SPMs that bind neutrophils, macrophages, and endothelial cells.

Activation of these receptors initiates anti-migratory signaling reducing neutrophil responsiveness to chemotactic signals. Inhibits neutrophil transmigration into tissues.

SPMs and inflammation

Do NOT suppress inflammation. They actively generate stop signals through receptors such as ALX/FPR2 that halt further neutrophil recruitment.

M1 macrophages

Fight

Produce the big 3 and ROS

Efficient at pathogen killing

Decrease SPM signaling

Can contribute to collateral tissue damage

M2 macrophages

Suppress inflammatory signaling

Produce IL-10 and TGF-B

Promote tissue remodeling and repair

Enhance clearance of apoptotic cells

Restore tissue homeostasis

Macrophage reprograming

Inflammation resolves because macrophages are actively reprogrammed from M1 destructive into M2 repair

Efferocytosis

Cleaning up the battlefield

M2 macrophages recognize and engulf apoptotic neutrophils

The immune systems cleaning service allowing inflammation to safety end without causing additional damage

Benefits of efferocytosis

Prevents release of toxic neutrophil contents

Limits tissue damage and fibrosis

Prevents secondary necrosis

Removes inflammatory debris

Accelerates restoration of normal tissue function

Without efferocytosis

Dying neutrophils undergo necrosis

Release proteases, ROS, and DAMPs

Chronic Inflammation is sustained

Tissue injury worsens

Chronic Inflammation

Failed resolution.

Many chronic diseases result from an inability to activate pro-resolving pathway

Leads to persistent neutrophil and macrophage activation, ongoing cytokine production, tissue destruction, fibrosis and loss of organ function.

Pro ressolving Vs Anti inflammatory

Aspirin

Does more than block COX. It irreversibly blocks COX so that PGs can not be formed. Instead aspiring triggered lipoxins are formed. So aspirin promotes both anti inflammation and pro resolving