Chronic Inflammation

Slide 1 · Chronic Inflammation

Persistent stimuli, tissue injury, and attempted repair

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain chronic inflammation as simultaneous inflammation, damage, and repair.

Distinguish its main causes and histologic pattern from acute inflammation.

Describe macrophage–lymphocyte interactions and activation programs.

Recognize granulomatous inflammation and its diagnostic implications.

Slide 3 · A prolonged response—not merely prolonged time

Chronic inflammation persists for weeks or months because the stimulus is sustained or poorly eliminated.

Inflammation and parenchymal injury occur alongside attempts at tissue healing.

It may follow an acute episode or begin without a clinically apparent acute phase.

Slide 4 · Three processes coexist in the same lesion

Inflammatory cell recruitment and activation

Injury to the original tissue

Angiogenesis and fibrosis during repair

Concurrent or complementary components of the host response

Slide 5 · Chronic inflammation can begin by two routes

After acute inflammation

Persistence of the injurious stimulus prevents complete resolution.

Example: Acute bacterial pneumonia progressing to a chronic lung abscess.

Insidious onset

A sustained immune or toxic stimulus produces a prolonged response from the outset.

Example: An evolving autoimmune or particle-related lesion.

Slide 6 · Acute versus chronic: Predominant cellular pattern

Acute response

Vascular changes and edema are prominent.

Neutrophils usually dominate the early infiltrate.

Chronic response

Macrophages, lymphocytes and plasma cells accumulate.

Tissue loss and fibrosis often coexist with ongoing recruitment.

Slide 7 · Possible outcomes of an acute inflammatory focus

Acute inflammatory reaction

Elimination of stimulus → resolution

Extensive injury → fibrosis / scar

Persistent stimulus → chronic inflammation

Mechanistic sequence — schematic

Slide 8 · Why chronic inflammation persists

Difficult-to-eradicate stimulus

Repeated immune activation

Continued leukocyte recruitment

Further tissue injury and repair

Mechanistic sequence — schematic

Slide 9 · Three major classes of persistent stimuli

Infections that resist clearance

Hypersensitivity or dysregulated immune reactions

Prolonged exposure to toxic materials

Concurrent or complementary components of the host response

Slide 10 · Persistent infection sustains cellular immunity

Mycobacteria and some viruses, fungi, and parasites are difficult to eliminate.

Persistent microbial antigens may elicit T-lymphocyte responses of the delayed-type hypersensitivity pattern.

Some infections evoke granulomatous inflammation to contain the stimulus.

Slide 11 · Not all chronic infections form granulomas

Granulomatous pattern

Aggregates of activated macrophages, frequently with T lymphocytes.

Characteristic but not universal for persistent infections.

Nongranulomatous pattern

Diffuse or mixed inflammation may persist in tissues.

The morphologic pattern depends on the agent and host response.

Slide 12 · Unresolved bacterial infection: A lung-abscess example

Acute bacterial pulmonary infection

Failure to eliminate the nidus

Ongoing purulent injury

Chronic abscess with persistent inflammation

Mechanistic sequence — schematic

Slide 13 · Hypersensitivity causes injury without useful clearance

Excessive or inappropriate activation of the immune system can maintain chronic inflammation.

The trigger may be a self-antigen, microbial component, or ordinary environmental substance.

Persistent immune activation can damage otherwise viable host tissues.

Slide 14 · Autoimmune inflammation is self-perpetuating

Self-antigen

Activation of T and B lymphocytes

Sustained inflammatory mediators

Tissue injury → continued antigen availability

Mechanistic sequence — schematic

Slide 15 · Examples of autoimmune chronic inflammation

Rheumatoid arthritis: An immune response in joint tissues is associated with chronic inflammation.

Multiple sclerosis: Immune responses against the nervous system produce tissue injury.

Autoantigen-driven lymphocyte activation can create a continuing disease process.

Slide 16 · Dysregulated responses to microbes

Not every inflammatory injury reflects ongoing invasive infection.

Inflammatory bowel disease exemplifies an inappropriate immune response to microbial antigens.

The resulting reaction can persist because the immune stimulus is continually present.

Slide 17 · Allergic inflammation: Ordinarily harmless antigens

Environmental substances may provoke disproportionate immune responses.

Bronchial asthma is an example in which immune activation drives tissue inflammation.

Repeated exacerbations can produce mixed acute and chronic patterns.

Slide 18 · Repeated flares may obscure an acute–chronic boundary

During exacerbation

Freshly recruited acute inflammatory cells may accompany an established chronic infiltrate.

One biopsy can show an active mixed-cell pattern.

Late-stage evolution

Connective tissue deposition may become prominent.

Fibrosis is evidence of sustained injury and repair, not necessarily inactivity.

Slide 19 · Inhaled silica: A nondegradable foreign stimulus

Particulate silica exposure

Persistent material in pulmonary tissue

Chronic inflammatory response

Fibrosing lung injury (silicosis)

Mechanistic sequence — schematic

Slide 20 · Endogenous lipids can maintain inflammation

Excessive cholesterol and lipid accumulation

Deposition in the arterial wall

Local chronic inflammation

Contribution to atherosclerotic plaque biology

Mechanistic sequence — schematic

Slide 21 · The inciting agent predicts the immune pattern

Setting

Main driver

Tissue response

Persistent microbe

T lymphocytes / macrophages

Sometimes granulomas

Self or environmental antigen

Activated lymphocytes ± eosinophils

Chronic or recurrent inflammation

Toxic particle or lipid

Macrophage-rich tissue response

Damage with fibrotic repair

Slide 22 · Three histologic hallmarks of chronic inflammation

Mononuclear cell infiltration

Destruction of tissue architecture

Repair: Small vessels and collagen deposition

Concurrent or complementary components of the host response

Slide 23 · Mononuclear infiltrate: Identify the cells

Macrophages are major phagocytic and secretory effectors.

Lymphocytes amplify antigen-specific immune responses.

Plasma cells reflect antibody-secreting B-cell differentiation.

The mixture varies according to the etiology and tissue.

Slide 24 · Tissue destruction identifies ongoing injury

Persistent offending stimulus

Activated inflammatory cells

Toxic mediators and enzymes

Loss of normal parenchymal architecture

Mechanistic sequence — schematic

Slide 25 · Angiogenesis is part of attempted repair

Small new vessels proliferate as the damaged tissue attempts to heal.

Angiogenesis can coexist with dense inflammatory infiltrates.

Repair features should be assessed together with the extent of parenchymal loss.

Slide 26 · Fibrosis replaces tissue that cannot regenerate fully

Collagen deposition can substitute for irreversibly destroyed parenchyma.

The resulting scar may impair specialized organ function.

Marked fibrosis may dominate older or recurrent lesions.

Slide 27 · How to read a chronic inflammatory biopsy

Cell-rich focus

Locate mononuclear-cell-rich areas.

Lost architecture

Look for loss of normal tissue units.

Fibrous repair

Identify fibroblasts, vessels and collagen-rich replacement.

Schematic only — not a histologic specimen

Slide 28 · A mixed infiltrate does not exclude chronicity

Neutrophils may remain when microorganisms or irritating stimuli persist.

Repeated injury can recruit fresh acute inflammatory cells into chronic lesions.

Classify the full tissue response rather than treating one cell type as decisive.

Slide 29 · Macrophages coordinate injury and repair

Destroy microbes and dead cells

Communicate through cytokines and antigen display

Recruit repair programs and connective-tissue deposition

Concurrent or complementary components of the host response

Slide 30 · The mononuclear phagocyte system

Hematopoietic progenitor

Blood monocyte

Tissue macrophage

Organ-specific macrophage population

Mechanistic sequence — schematic

Slide 31 · Circulating monocytes enter inflamed tissues

Marrow-derived monocyte in blood

Adhesion and chemotaxis

Transmigration through endothelium

Differentiation and local macrophage activity

Mechanistic sequence — schematic

Slide 32 · Not all tissue macrophages derive from adult monocytes

Monocyte-derived

Adult marrow progenitors generate blood monocytes.

Important in inflammatory foci and some renewing tissue sites.

Embryonically seeded

Yolk-sac or fetal-liver progenitors seed selected organs.

Long-lived resident cells can persist in the tissue.

Slide 33 · Organ-specific macrophage populations

Tissue

Cell name

Function

Liver

Kupffer cells

Resident parenchymal surveillance

Brain

Microglia

Resident immune surveillance

Lung

Alveolar macrophages

Airspace defense and debris clearance

Slide 34 · Recruitment and lifespan differ by compartment

Blood monocytes are short-lived relative to many tissue macrophages.

In an inflammatory lesion, monocytes can become the dominant population within about 48 hours.

Resident macrophages may be maintained for extended periods in their organ.

Slide 35 · Macrophages execute three connected functions

Phagocytosis and microbial killing

Cytokine and lipid-mediator secretion

Regulation of healing and scar formation

Concurrent or complementary components of the host response

Slide 36 · Proinflammatory macrophage secretions

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) amplify inflammation.

Chemokines guide additional leukocytes into the tissue.

Eicosanoids also participate in inflammatory mediator networks.

Slide 37 · Antigen display activates adaptive immunity

Macrophage processes antigen

Antigen display and costimulation

Activated T lymphocyte

Cytokines feed back to macrophage

Mechanistic sequence — schematic

Slide 38 · Classical activation: Initiating signals

Microbial products activate innate sensors such as toll-like receptors (TLRs).

T-cell-derived interferon-γ (IFN-γ) is a major activating cytokine.

Crystals and other particulates can also drive classical activation.

Slide 39 · Classical activation favors host defense

Microbial products / IFN-γ

Classically activated macrophage (M1-like)

ROS • NO • lysosomal enzymes

Microbial killing and increased inflammation

Mechanistic sequence — schematic

Slide 40 · Alternative activation: Initiating signals

Interleukin-4 (IL-4) and IL-13 can induce an alternative macrophage program.

These mediators are often produced by Th2 cells and other immune cells.

Alternative activation is linked more strongly to resolution and tissue repair than to direct microbial killing.

Slide 41 · Alternative activation favors tissue reconstruction

IL-4 / IL-13

Alternatively activated macrophage (M2-like)

Signals to fibroblasts and repair cells

Inflammation termination and scar formation

Mechanistic sequence — schematic

Slide 42 · M1-like and M2-like responses: Functional poles

M1-like

Driven by microbial products or IFN-γ.

Microbicidal substances and inflammatory cytokines.

M2-like

Driven by cytokines including IL-4 and IL-13.

Resolution-associated activity and tissue repair.

Slide 43 · M1/M2 are models, not rigid cell diagnoses

Actual inflammatory tissues often contain mixed activation states.

Many intermediate macrophage phenotypes cannot be reliably assigned to a binary subset.

A universal sequence of M1 followed by M2 has not been documented across most lesions.

Slide 44 · Macrophage defense can become collateral injury

Persistent or excessive activation

Continuous oxidant / enzyme release

Damage to nearby viable tissue

Further inflammation and reparative fibrosis

Mechanistic sequence — schematic

Slide 45 · Why macrophages remain in chronic lesions

Persistent recruitment of circulating monocytes replenishes the infiltrate.

Local macrophage proliferation can sustain the population.

After stimulus removal, macrophages may die or exit via lymphatic drainage.

Slide 46 · T and B lymphocytes amplify chronic inflammation

Microbial and environmental antigens stimulate lymphocyte responses.

Activated T cells generate cytokines that recruit and alter macrophage behavior.

Long-lived memory lymphocytes can help sustain the reaction.

Slide 47 · CD4 T-cell subsets generate distinct inflammation

Th1 → IFN-γ → macrophage activation

Th2 → IL-4, IL-13, IL-5 → allergy / eosinophils

Th17 → IL-17 → chemokines / neutrophils

Concurrent or complementary components of the host response

Slide 48 · Th1 cells connect cellular immunity to macrophages

Persistent antigen activates Th1 cell

IFN-γ secretion

Classical macrophage activation

Microbial destruction ± host tissue injury

Mechanistic sequence — schematic

Slide 49 · Th2 mediators recruit distinct effectors

Th2 cells

IL-5 → eosinophil recruitment

IL-4 / IL-13 → IgE and alternative macrophage activation

Helminth defense or allergic disease

Mechanistic sequence — schematic

Slide 50 · Th17 cells recruit neutrophilic inflammation

Activated Th17 cell

IL-17 and related cytokines

Chemokine production in local tissues

Recruitment of neutrophils and monocytes

Mechanistic sequence — schematic

Slide 51 · T-helper pathways: Mediator to tissue phenotype

T-cell pathway

Downstream response

Pattern

Th1 / IFN-γ

Macrophage activation

Cell-mediated inflammation

Th2 / IL-4, IL-5, IL-13

IgE, eosinophils, M2-like signals

Allergic / helminth response

Th17 / IL-17

Chemokine-driven recruitment

Neutrophil-rich component

Slide 52 · The macrophage–T-cell feedback loop

Macrophage presents antigen

T cell receives IL-12 and signals

T cell releases IFN-γ and other mediators

Macrophage activation is reinforced

Slide 53 · Why adaptive immunity prolongs inflammation

Antigen presentation, costimulation and macrophage cytokines drive T-cell responses.

Activated T lymphocytes release cytokines that recruit and activate macrophages.

Persistent antigen closes the feedback loop and can support granuloma formation.

Slide 54 · Plasma cells reveal a humoral response

B lymphocytes may differentiate into antibody-secreting plasma cells at an inflamed site.

The antibodies can recognize persistent foreign antigens, self-antigens or altered tissue components.

The overall pathogenic contribution of local antibodies is uncertain in many conditions.

Slide 55 · Tertiary lymphoid structures can form in tissues

Lymphocytes, antigen-presenting cells and plasma cells may assemble into follicle-like structures.

Examples include rheumatoid synovium, Hashimoto thyroiditis and inflammation around some tumors.

Their role in perpetuating local immune responses remains incompletely established.

Slide 56 · Eosinophils contribute to chronic allergic injury

Th2 cytokines and eotaxin

Eosinophil recruitment

Major basic protein release

Helminth toxicity plus possible epithelial injury

Mechanistic sequence — schematic

Slide 57 · Mast cells can sustain inflammatory signaling

Tissue mast cells express the high-affinity IgE receptor FcεRI.

Antigen engagement of surface-bound IgE can release histamine and prostaglandins.

Mast-cell-derived cytokines may also contribute to chronic inflammatory lesions.

Slide 58 · Neutrophils may persist for months

Neutrophils are not restricted to purely acute lesions.

Chronic osteomyelitis may show prolonged purulent inflammation.

Smoking-related pulmonary injury may also involve continuing neutrophilic damage.

Slide 59 · Granulomas attempt to contain resistant agents

Hard-to-eliminate stimulus

Strong macrophage and T-cell activation

Aggregates of epithelioid macrophages

Containment with potential tissue injury

Mechanistic sequence — schematic

Slide 60 · Two major pathogenetic classes of granulomas

Foreign-body granuloma

Inert, large, poorly phagocytosed material.

May develop without a specific T-cell immune response.

Immune granuloma

Persistent microbe or antigen activates T cells.

Cytokine-driven macrophage activation is central.

Slide 61 · Foreign-body granuloma: Material at the center

Suture / talc / other fiber

Material resists engulfment

Macrophages and giant cells surround it

Refractile material may be seen with polarized light

Mechanistic sequence — schematic

Slide 62 · Immune granuloma: A T-cell-driven arrangement

Persistent antigen

Th1-associated response / IFN-γ

Activated macrophages become epithelioid

Compact granuloma forms

Mechanistic sequence — schematic

Slide 63 · Basic granuloma architecture

Optional necrosis

Organized inflammatory focus

Epithelioid macrophage center

Peripheral lymphocyte collar

Sometimes giant cells, necrosis and fibrosis

Schematic only — central necrosis is not obligatory

Slide 64 · Epithelioid cells are activated macrophages

Activated macrophages acquire abundant granular, pink cytoplasm on H&E sections.

Cellular outlines may become indistinct in tightly packed epithelioid clusters.

The name reflects their epithelial-like appearance, not epithelial lineage.

Slide 65 · Multinucleated giant cells arise by fusion

Some activated macrophages fuse to form large multinucleated cells.

Langhans-type giant cells contain many nuclei, often arranged near the periphery.

Giant cells support a granulomatous pattern but are not invariably present.

Slide 66 · Central necrosis is an important descriptor

Caseous necrosis shows granular, acellular eosinophilic debris and loss of cell outlines.

Mycobacterium tuberculosis is a prototypical cause of necrotizing granulomas.

The presence or absence of necrosis alone does not identify the etiology.

Slide 67 · Necrotizing and nonnecrotizing patterns

Necrotizing

A central zone of amorphous, structureless necrotic debris.

Can be found in tuberculosis and other infections.

Nonnecrotizing

Epithelioid aggregates without a central necrotic focus.

May occur in sarcoidosis, Crohn disease or foreign-body reactions.

Slide 68 · Granulomatous diseases: Targeted examples

Condition

Known cause

Typical pattern

Tuberculosis

Mycobacterium tuberculosis

Often necrotizing granulomas

Sarcoidosis

Etiology unknown

Often nonnecrotizing granulomas

Crohn disease

Dysregulated intestinal immune response

Occasional nonnecrotizing granulomas

Slide 69 · Granulomas require an etiologic work-up

Recognize granulomatous histology

Evaluate clinical and anatomic context

Organism stains / culture / molecular testing

Integrate results; Exclude tuberculosis when relevant

Mechanistic sequence — schematic

Slide 70 · Granuloma ≠ granulation tissue

Granuloma

Organized cluster of epithelioid macrophages.

Immune or foreign-body response to a persistent stimulus.

Granulation tissue

New capillaries, fibroblasts and loose extracellular matrix.

A reparative tissue that forms during wound healing.

Slide 71 · Systemic inflammation can accompany local lesions

Cytokines released during inflammation have effects beyond the affected organ.

TNF, IL-1 and IL-6 contribute to systemic inflammatory reactions.

Acute-phase protein concentrations may rise during chronic as well as acute inflammation.

Slide 72 · CRP and fibrinogen reflect acute-phase signaling

Inflammatory cytokines (especially IL-6)

Hepatocyte acute-phase response

C-reactive protein and fibrinogen

CRP measurement and erythrocyte sedimentation response

Mechanistic sequence — schematic

Slide 73 · Sustained SAA production can cause amyloid deposition

Persistent inflammation

Prolonged serum amyloid A production

AA amyloid deposition

Additional organ dysfunction

Mechanistic sequence — schematic

Slide 74 · Clinicopathologic example: Pulmonary granuloma

Observation

Biopsy: Clusters of epithelioid histiocytes with necrotic centers.

Interpretation

Interpretation: Necrotizing granulomatous inflammation; Infection is a major consideration.

Next diagnostic principle

Next step: Evaluate for organisms with appropriate stains and microbiologic tests.

Slide 75 · Clinicopathologic example: Persistent synovitis

Observation

Joint tissue contains lymphocytes, plasma cells and macrophages with fibrosis.

Interpretation

Interpretation: Chronic immune-mediated injury and repair can coexist.

Next diagnostic principle

The infiltrate alone does not establish a specific diagnosis without clinical correlation.

Slide 76 · Clinicopathologic example: Foreign material

Observation

A lesion contains multinucleated giant cells adjacent to identifiable suture material.

Interpretation

Interpretation: A foreign-body granulomatous response is favored.

Next diagnostic principle

Use polarization and the clinical history to evaluate retained material.

Slide 77 · Integrated mechanism of chronic injury

Persistent antigen / microbe / toxic stimulus

Leukocyte recruitment and activation

Mediator-driven injury to tissue

Concurrent angiogenesis and fibrosis

Mechanistic sequence — schematic

Slide 78 · Five distinctions to retain

Chronic inflammation is defined by an ongoing response, not by a fixed number of days.

Mononuclear cells, tissue destruction and repair form its characteristic histologic triad.

Macrophages can eliminate agents and simultaneously damage host parenchyma.

T-cell–macrophage feedback explains persistence in many immune-driven lesions.

A granuloma is a specific reaction pattern, not a final etiologic diagnosis.

Slide 79 · Reference

Primary textbook and material

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

Inflammation and Repair: chronic inflammation, granulomatous inflammation, and systemic consequences.

All diagrams are explanatory schematics, not histopathology specimens.