Inflammation and Repair

General Pathology

This is a protective response of vascularized tissues to infection or tissue injury. It involves the movement of leukocytes and other host-defense molecules from circulation to the site of infection of cell damage.

Inflammation

The main purpose of inflammation is to:

Eliminate the offending agent and initiate tissue repair

What are the 3 important mediators of inflamamtion?

1. Leukocytes

2. Antibodies

3. Complement proteins

These are immune cells that help eliminate the offending agent

Leukocytes

These recognize and help neutralize foreign substances

Antibodies

These proteins enhance the immune response and help destroy pathologens

Complement proteins

What are the 5 steps of inflammation?

1. Recognition of the noxious agent

2. Recruitment of leukocytes

3. Removal of stimulus

4. Regulation

5. Repair

What occurs in the first step of inflammation?

1. Recognition of the noxious agent

• Tissue-resident sentinel cells recognize harmful stimuli.

• These cells contain receptors that detect:

  • Microbial products

  • Substances released from dead or damaged cells

• Think: “Sentinel cells are waiting and watching for danger.”

What occurs in the 2nd step of inflammation?

2. Recruitment of leukocytes

• Signals released by sentinel cells recruit leukocytes from the circulation to the site of injury.

• Neutrophils are usually the first leukocytes recruited.

• They move from the blood to the extravascular site of the noxious stimulus.

What occurs in the 3rd step of inflammation?

3. Removal of the stimulus

• Mainly performed by phagocytic cells.

• These cells ingest and destroy microbes and cellular debris.

What occurs in the 4th step of inflammation?

4. Regulation

• Once the harmful stimulus is eliminated, mechanisms work to stop or limit the inflammatory response.

• Continuous inflammation is harmful and can cause tissue damage.

What occurs in the 5th step of inflammation?

5. Repair

• The final step involves processes that heal the damaged tissue and restore tissue structure and function.

What occurs during healing by first intention?

First intention

• Wound edges are brought together (e.g., sutures).

• Small tissue defect → small scar → faster healing.

What occurs during healing by 2nd intention?

Second intention

• Wound edges cannot be brought together.

• Larger defect → more scar tissue → slower healing.

• Wound closure involves myoepithelial cell recruitment and contraction of surrounding tissue.

What are 2 types of excessive scarring?

1. Hypertrophic scars

2. Keloids

This is excessive scar tissue, usually within the wound.

Hypertrophic scarring

This is scar tissue that extends beyond the original wound, more common in people of African ancestry.

Keloid scarring

What factors may affect tissue repair?

Factors Affecting Tissue Repair

• Infection → delays healing.

• Diabetes → causes abnormal/impaired wound healing.

• Nutrition → vitamin C deficiency inhibits collagen formation.

• Glucocorticoids → reduce inflammation but inhibit TGF-β, weakening the scar and reducing scar formation.

• Poor perfusion → reduces healing due to inadequate blood supply (e.g., peripheral vascular disease).

• Foreign bodies → prolong inflammation and impair healing.

• Extent & type of injury → injury to permanent tissues (e.g., limb amputation) requires prolonged healing.

• Location of injury → affects outcome; e.g., small pleural effusions may resolve completely, while large effusions can organize and cause scarring.

ECM deposition occurs in what 2 steps?

1. Fibroblast migration → fibroblasts move to the site of injury.

2. ECM protein deposition → fibroblasts produce and deposit extracellular matrix proteins.

What are the main mediators of ECM deposition?

Main mediators: PDGF, FGF-2, and TGF-β

What is the most important cytokine for ECM deposition and why?

• TGF-β is the most important cytokine for connective tissue deposition.

• It initiates and regulates the amount of connective tissue formed.

What are the steps of angiogenesis?

1. Vasodilation → mediated by NO and VEGF.

2. Pericyte separation + basement membrane breakdown → allows vessel sprouting.

3. Endothelial cell migration → cells move toward the injured tissue.

4. Endothelial cell proliferation → occurs behind the migrating cells.

5. Remodeling → endothelial cells form capillary tubes.

6. Pericyte & smooth muscle recruitment → stabilizes the new vessel.

7. Maturation → endothelial proliferation/migration stops and basement membrane is deposited.

This is the formation of new blood vessels from pre-existing vessels

Angiogenesis

What are the 2 major mechanisms in tissue repair?

1. Regeneration

2. Connective tissue deposition (scar formation)

What is the first step of tissue repair?

. Regeneration

• Damaged cells are replaced by new cells of the same type.

• Requires cell proliferation, driven by growth factors and supported by the ECM.

• Tissue stem cells can also produce mature cells.

• Labile tissues → continuously divide.

• Stable tissues → normally in G₀, but can divide after injury.

• Permanent tissues → have little/no capacity to replicate (e.g., neurons).

• Example: the liver can regenerate after partial removal.

What occurs in the 2nd step of tissue repair?

2. Connective Tissue Deposition (Scar Formation)

• Occurs when tissue damage is too severe for regeneration.

• Macrophages clear the necrotic tissue, followed by:

  • Growth of new blood vessels

  • Fibroblast/ECM deposition

  • Collagen scar formation

  • Re-epithelialization of the surface

Even if inflammation is localized, it can cause this systemic reaction response:

Acute-phase response

What occurs during the acute-phase response of inflammation?

• Fever → caused by pyrogens, mainly IL-1 and TNF, which act on the hypothalamus.

• Acute-phase proteins increase → especially CRP and fibrinogen; IL-6 is an important mediator of their production.

• ↑ Pulse, blood pressure, chills, and other systemic effects → result from cytokine actions.

• CRP → commonly used clinically as a marker of inflammation.

• ESR (erythrocyte sedimentation rate) → another marker of inflammation; increased fibrinogen promotes RBC aggregation, causing them to settle faster.

• Leukocytosis → increased WBC count, commonly seen with infections.

  • Initially due to release of bone marrow WBC stores, stimulated by TNF and IL-1.

This inflammation is characterized by collections of activated macrophages, often with T lymphocytes and sometimes necrosis.

Chronic inflammation

What are the two types of granulomas?

1. Foreign body granulomas

2. Immune granulomas

What causes foreign body granulomas?

• Caused by inert foreign materials that trigger inflammation without a specific T-cell–mediated immune response.

• Examples: splinter, hernia mesh.

• Think: “The body walls it off.”

What causes immune granulomas?

• Caused by agents that produce a persistent T-cell–mediated immune response.

• Th1 cells → IFN-γ → macrophage activation.

• Examples:

  • Tuberculosis

  • Leprosy

  • Syphilis

  • Cat-scratch disease

  • Fungal infections

• Can also occur in noninfectious diseases, such as sarcoidosis and Crohn disease.

What is eosinophils role in chronic inflammation?

• Abundant in IgE-mediated immune reactions, especially parasitic infections and allergies.

• Recruited by vascular adhesion molecules and the chemokine eotaxin.

• Granules contain major basic protein (MBP), which is toxic to helminths (worms) but can also damage host tissues.

What is the role of mast cells in chronic inflammation?

• Widely distributed throughout tissues.

• Surface Fc receptors bind the Fc portion of IgE.

• When IgE recognizes an antigen, mast cells degranulate.

• Can cause severe allergic reactions, such as a peanut allergy.

What is the role of neutrophils in chronic inflammation?

Neutrophils

• Classically associated with acute inflammation.

• Can also persist in chronic inflammation when the injurious stimulus remains.

• Their continued activity can contribute to tissue damage.

These cells help amplify and maintain chronic inflammation and form memory cells, allowing for faster response to future exposure

Lymphocytes

These are helper cells that produce cytokines and determine the type of inflammatory response.

CD4+ T cells

What is the function of the Th1 → IFN-γ → M1 macrophages?

• Activates macrophages through the classical pathway.

• Important for microbial killing.

What is the function of the Th2 → IL-4, IL-5, IL-13 → M2 macrophages + eosinophils?

• Activates the alternative pathway.

• Important in parasite/helminth infections and allergic reactions.

What is the function of the Th17 → IL-17 → neutrophils + monocytes?

• Stimulates production of chemokines that recruit neutrophils and monocytes.

These cells produce antibodies against persistent foreign antigens.

B lymphocytes

B lymphocytes may accumulate in inflamed tissue and form:

Lymphoid follicles

What is the classical Activation (M1) pathway?

• Induced by microbial products that activate TLRs and by T-cell cytokines, especially IFN-γ.

• M1 macrophages produce NO and lysosomal enzymes to kill ingested microbes.

• Main role: host defense.

• Can also cause tissue injury if activation persists.

What is the alternative activation (M2) pathway?

• Induced by cytokines such as IL-4 and IL-13 produced by T lymphocytes.

• M2 macrophages are not strongly microbiocidal.

• Help terminate inflammation and promote tissue repair.

Where are macrophages derived from?

from monocytes in the bone marrow

What are the man functions of macrophages?

Secrete cytokines → recruit and activate other inflammatory cells and promote tissue repair.

• Kill microbes → release substances that directly destroy microorganisms.

• Phagocytosis → ingest and destroy microbes and cellular debris.

• Antigen presentation → present antigens to T cells, directing T-cell–mediated immune responses.

What are the 3 main characteristics of chronic inflammation?

1. Mononuclear cell infiltration

   • Macrophages (monocytes)

   • Lymphocytes

   • Plasma cells

2. Tissue destruction

• Caused by a persistent offending agent and the ongoing inflammatory response.

3. Attempts at healing

• Damaged tissue is replaced by connective tissue, leading to fibrosis/scar formation.

What are the 3 outcomes of acute inflammation?

1. Complete resolution (MOST PREFERRED)

2. Healing by connective tissue repair (scar formation)

3. Progression to chronic inflammation

What occurs in complete resolution of acute inflammation?

• Normal tissue is restored after the offending stimulus is eliminated.

• Occurs when the injury is limited and short-lived.

• No significant scar formation.

What occurs in the healing by connective tissue repair outcome of acute inflammation?

• Connective tissue replaces damaged tissue when normal regeneration is not possible.

• Occurs with substantial tissue destruction.

What occurs in the progression to chronic inflammation outcome of acute inflammation?

• Acute inflammation transitions to chronic inflammation when the injurious agent persists and the response cannot be resolved.

• Characterized by mononuclear cells such as macrophages and lymphocytes.

This acute inflammation morphological pattern is cell-poor fluid that leaks from blood vessels due to increased vascular permeability (pleural effusion, ascites)

Serous inflammation

this acute inflammation morphological pattern occurs when vascular leakage is more severe or there is a local procoagulant stimulus (“Bread-and-Butter” pericarditis)

Fibrinous inflammation

This acute inflammation morphological pattern occurs with pus that contains a large amount of neutrophils. The neutrophils will form an abscess. Ulcers will also cause erosion, causing neutrophilic accumulation.

Purulent (suppurative) inflammation

What are 4 other inflammatory mediators?

1. Platelet-Activating Factor (PAF)

2. Coagulation Products

3. Kinins

4. Neuropeptides

How does PAF mediate inflammation?

Causes vasodilation and increased vascular permeability (produced by many cell types)

How does coagulation products mediate inflammation?

Activate platelets and contribute to inflammation

Generated during blood clotting

How does kinins mediate inflammation?

• Vasoactive peptides produced from kininogen by the enzyme kallikrein.

• Kallikrein → Bradykinin

• Bradykinin causes vasodilation and pain.

How does neuropepties mediate inflammation?

• Substance P and neurokinin A are released by neurons.

• Important in pain signaling.

• Leukocytes have receptors for neuropeptides, allowing communication between the nervous and inflammatory systems.

C1 inhibitor blocks

C1 activation (resulting in hereditary angiodema)

Decay-accelerating factor (DAF) prevents

the formation of C3 convertase

CD59 inhibits:

the formation of the membrane attack complex

Complement factor H promotes:

breakdown of C3b and turnover of C3 convertase, which can cause hemolytic uremic syndrome

What is the classical complement system pathway?

• C1 binds to antibody-antigen complexes.

• Mainly involves IgG and IgM.

• Classical = Antibody

What is the alternative complement system pathway?

2. Alternative pathway

• Triggered directly by microbial surface molecules.

• Examples include endotoxins and lipopolysaccharides (LPS).

• Alternative = Microbes

What is the lectin complement system pathway?

• Mannose-binding lectin (MBL) binds to carbohydrates on microbial surfaces.

• Activates complement without antibodies.

• Lectin = Mannose

This is a group of plasma proteins involved in host defense against microbes and inflammatory reactions

Complement system

These are small proteins that act as chemoattractants, directing specific types of leukocytes to sites where they are needed

chemokines

How do chemokines mediate their activity?

• They act by binding to G-protein–coupled receptors (GPCRs) on leukocytes.

• Some chemokine receptors can also act as co-receptors for viral entry, including HIV.

What is the role of chemokines in inflammation?

• During acute inflammation, microbes stimulate chemokine production.

• Chemokines help activate leukocytes and increase their adhesion to endothelial cells, allowing them to leave the bloodstream and enter tissues.

These chemokines help organize immune cells within normal tissues, for example they help maintain the separate locations of T cells and B cells within lymph nodes.

Homeostatic chemokines

These are proteins that are produced by many cell types that regulate and mediate immune and inflammatory responses (like TNF and IL-1)

cytokines

What are the main functions of TNF and IL-1?

• Promote leukocyte adhesion to endothelial cells, helping leukocytes migrate from the blood into tissues.

• Activate endothelial cells by increasing adhesion molecules, including E-selectin and P-selectin.

• Enhance neutrophil responses to stimuli such as bacterial toxins.

• Increase macrophage microbiocidal activity by promoting NO production.

• Activate fibroblasts, increasing collagen production and contributing to tissue repair.

What is clinically significant of TNF antagonists?

They block TNF activity and are effective treatments for chronic inflammatory diseases such as rheumatoid arthritis

These are derived from arachidonic acid through the action of lipoxygenase

Lipoxins

Lipoxins production require two cell types:

1. Neutrophils produce precursors.

2. Platelets convert these precursors into active lipoxins.

Lipoxins are anti-inflammatory mediators, so their function is:

• They inhibit neutrophil chemotaxis and adhesion to endothelial cells, helping to limit inflammation.

Leukotrines are produced by:

Leukocytes from arachidonic acid, through lipoxygenase pathway

What are the 3 lipoxygenases?

LTB4

• Formed from 5-HETE.

• Chemotactic for neutrophils.

• Activates neutrophils and promotes their adhesion to venular endothelium.

LTC4, LTD4, LTE4

• Cause vasoconstriction.

• Cause powerful bronchoconstriction (bronchospasm).

• Increase vascular permeability.

• Are more potent than histamine in causing increased vascular permeability and bronchospasm.

this is a 20-carbon polyunsaturated fatty acid found in the cell membrane phospholipids

Arachidonic acid (AA)

Leukotrines are produced by:

LOX PATHWAY

Mainly by leukocytes and mast cells

Prostagladins are produced by:

COX PATHWAY

Mast cells, macrophages, endothelial cells, and other cells

Histamine is mainly stored in mast cell granules and are released in response to:

• Physical injury

• IgE–antigen reactions (allergies)

• Complement products C3a and C5a (anaphylatoxins)

A histamine reaction will cause:

• Vasodilation

• Increased vascular permeability, especially in venules

• Acts through histamine receptors on endothelial cells.

• Antihistamines block histamine receptors and are used to treat allergies.

• Example: Allergic nasal congestion results partly from histamine-induced vasodilation.

Serotonin is preformed and stored mainly in platelets and specialized neuroendocrine cells, such as

intestinal cells

Seratonin mainly acts as a:

Vasoconstrictor

What are the 2 types of mediators of inflammation?

1. Cell-derived mediators

2. Plasma-derived medators

What are cell-derived mediators?

• Some are preformed and stored in intracellular granules.

• They are released by exocytosis/degranulation when cells are activated.

• Example: histamine stored in mast cells.

• Mast cells act as sentinel cells, remaining in tissues and ready to release their mediators when activated.

What are plasma-derived mediators?

• Mostly complement proteins and other circulating proteins.

• Many are produced in the liver and circulate in inactive forms.

• They become active through a series of proteolytic reactions.

When does acute inflammation stop?

• The stimulus is terminated → no more signals recruit leukocytes.

• Neutrophils have a short half-life, so they quickly die and are cleared from the tissue.

• Macrophages release anti-inflammatory cytokines, mainly:

  • TGF-β

  • IL-10

• These cytokines suppress the inflammatory response and promote resolution.

What are neutrophil extracellular traps (NETs)?

• NETs are extracellular networks made of neutrophil DNA and histones.

What is the function of NETs?

• They trap microbes and concentrate antimicrobial substances, helping prevent the spread of infection.

• NET formation involves ROS-dependent activation of peptidylarginine deiminase (PAD), which converts arginine → citrulline.

• This causes chromatin decondensation, allowing the DNA to be released outside the cell.

• NETs may contribute to autoimmune disease by exposing nuclear antigens to the immune system.

What are the 2 granule types that neutrophils have to kill microbes?

1. Secondary granules (smaller)

2. Primary (azurophilic) granules, larger

what enzymes are within the secondary granules of neutrophils?

• Lysozyme

• Collagenase

• Gelatinase

• Lactoferrin

• Plasminogen activator

• Histaminase

• Alkaline phosphatase

What enzymes are within the primary granules of neutrophils?

• Myeloperoxidase (MPO)

• Lysozyme

• Defensins

• Acid hydrolases

• Other bactericidal proteins

Can neutrophil enzymes damage surrounding tissue if released outside the cell?

• Neutrophil enzymes can damage surrounding tissue if released outside the cell.

• Plasma contains inhibitors such as α1-antitrypsin and α2-macroglobulin that help neutralize these enzymes