Chronic Inflammation and Scarring

Slide 1 · Chronic Inflammation and Scarring

The host response, the scar, and the organ consequence

Persistent infection

Chronic injury

Fibrous repair

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Identify the morphologic triad of chronic inflammation.

Explain how persistent infection drives fibrotic repair.

Relate HBV, schistosome infection, and tuberculosis to organ-specific scarring.

Distinguish fibrosis, granulomatous inflammation, and regenerative nodularity.

Slide 3 · A chronic infection can outlast its initial inflammatory response

Persistent agent

Sustained host response

Tissue injury and repair

Fibrosis or altered architecture

Causal sequence (schematic)

Slide 4 · Two distinct endpoints of long-standing inflammation

Healing with preserved function

Excessive scarring with dysfunction

Offending stimulus controlled

Inflammation persists or injury is extensive

Parenchyma and matrix substantially restored

Collagen replaces or distorts functional tissue

Architecture remains usable

Vessels, ducts, or chambers may be compromised

Slide 5 · Chronic inflammation is defined by simultaneous processes

Inflammation, tissue destruction, and attempted repair occur together.

The process may follow acute inflammation or begin insidiously.

Its defining feature is persistence, not simply the age of a lesion.

Slide 6 · The microscopic triad of chronic inflammation

Mononuclear inflammatory infiltrate

Ongoing tissue destruction

Repair by angiogenesis and fibrosis

These three processes can be active in the same tissue section.

Slide 7 · Acute and chronic inflammation have different signatures

Acute inflammation

Chronic inflammation

Vascular change and edema prominent

Mononuclear cell infiltration prominent

Neutrophils often dominate

Macrophages, lymphocytes, plasma cells

May resolve completely

Tissue injury and repair coexist

Fibrosis not a defining feature

Fibrosis may be marked

Slide 8 · Persistent microbes are one major initiating category

Mycobacteria, certain viruses, fungi, and parasites can resist eradication.

Ongoing antigen exposure sustains lymphocyte–macrophage responses.

Some persistent infections produce granulomas; Others cause diffuse inflammation.

Slide 9 · Why repeated episodes amplify tissue damage

Persistent microbial stimulus

Recurrent immune-cell recruitment

Repeated parenchymal injury

Repair → cumulative matrix deposition

Causal sequence (schematic)

Slide 10 · A chronic lesion is not simply “full of lymphocytes”

Macrophages, lymphocytes, and plasma cells form the characteristic infiltrate.

Destruction may be caused by microbes and by host inflammatory cells.

Fibroblasts, new vessels, and collagen indicate concurrent repair.

Slide 11 · The cellular infiltrate offers clues—not an organism ID

Pattern

Interpretation in infectious pathology

Lymphocyte rich

Cell-mediated responses, including chronic HBV

Plasma-cell rich

May be conspicuous in syphilis

Macrophage rich

Persistent intracellular microbes or granulomatous reaction

Eosinophils with granulomas

Consider helminth-associated responses such as schistosomiasis

Slide 12 · Tissue destruction may persist despite a robust response

Leukocytes release mediators that can injure adjacent normal cells.

Persistent microorganisms maintain inflammatory-cell activation.

Functional parenchymal loss reduces the capacity for complete restoration.

Slide 13 · Infection is one cause of a general fibrotic response

Microbial injury

Host inflammation

Fibroblast activation

Collagen-rich scar

Causal sequence (schematic)

Slide 14 · The outcome depends on both the organism and the organ

Microbial persistence determines duration of stimulation.

Host immunity influences whether inflammation becomes diffuse or granulomatous.

Preexisting tissue architecture determines what scarring obstructs or distorts.

Slide 15 · Granulomatous inflammation localizes persistent stimuli

Persistent stimulus

T-cell response

Activated macrophages

Epithelioid granuloma

Mechanistic schematic

Slide 16 · An epithelioid granuloma is an organized cell collection

Activated macrophages gain abundant cytoplasm and epithelioid morphology.

Some macrophages fuse into multinucleated giant cells.

Lymphocytes and fibroblasts may form a peripheral cuff.

Slide 17 · Granulation tissue and granuloma are not synonyms

Granulation tissue

Granuloma

New capillaries + proliferating fibroblasts

Aggregated activated macrophages

Loose ECM with inflammatory cells

Often epithelioid cells and giant cells

A component of tissue repair

A pattern of chronic inflammation

Can mature into scar

May coexist with surrounding fibrosis

Slide 18 · The Th1–macrophage circuit sustains some granulomas

Persistent microbial antigen

Th1 lymphocyte activation

Interferon-γ

Macrophage activation

Causal sequence (schematic)

Slide 19 · The same granuloma can protect and damage tissue

Containment helps localize agents resistant to elimination.

Activated macrophages may damage tissue during host defense.

Chronic granulomatous inflammation can be accompanied by fibrous repair.

Slide 20 · Granulomas are etiologic clues, not diagnoses

Tuberculosis is an important infection to exclude when granulomas are identified.

Noninfectious inflammatory diseases may also produce granulomas.

Special stains, microbiologic tests, or molecular assays can be needed to identify the cause.

Slide 21 · Different microbial reactions produce different patterns

Reactive pattern

Selected example

Suppurative inflammation

Pyogenic bacterial infections

Mononuclear / granulomatous

Tuberculosis, schistosome eggs

Cytopathic / cytoproliferative

Some viral infections

Necrosis-dominant

Toxin-associated infections

Chronic inflammation and scarring

HBV cirrhosis, schistosomal fibrosis

Slide 22 · Mixed tissue reactions are common in actual specimens

Several host-reaction patterns may coexist in a single infected organ.

The Robbins examples include simultaneous CMV and Pneumocystis pulmonary disease in AIDS.

Do not assign a specific organism using scar morphology alone.

Slide 23 · Macrophages connect antimicrobial defense to tissue repair

Remove microbes and dead cells

Produce cytokines and growth factors

Recruit fibroblasts and vessels

Regulate matrix deposition

Causal sequence (schematic)

Slide 24 · Macrophage activation: Useful functional extremes

Classical / M1-like

Alternative / M2-like

Induced by microbial signals and IFN-γ

Associated with IL-4 and IL-13

ROS, NO, lysosomal enzymes

Inflammation resolution and tissue repair

Microbial killing and inflammation

Fibroblast activation and ECM deposition

Slide 25 · M1/M2 should not be treated as fixed tissue identities

These labels as extreme conceptual phenotypes.

Many intermediate macrophage states occur in inflammatory lesions.

A strict temporal switch from M1 to M2 is not established for most reactions.

Slide 26 · T-cell signals modulate the repair environment

Th1 → IFN-γ

Macrophage antimicrobial activation

Th2 → IL-4 / IL-13

Repair-associated macrophage responses

Mechanistic schematic

Slide 27 · Regeneration and scarring solve different problems

Regeneration replaces cells with the tissue’s own cell types.

Scar formation replaces damaged structures with connective tissue.

A scar repairs continuity but cannot necessarily restore specialized function.

Slide 28 · Preserved versus destroyed connective-tissue framework

Framework relatively intact

Framework severely disrupted

Surviving cells can proliferate on a usable scaffold

Replacement requires more connective tissue

Regeneration may predominate

Scar formation becomes more important

Normal relationships more likely to recover

Architectural distortion may persist

Slide 29 · The sequence of connective-tissue repair

Inflammatory cleanup

Angiogenesis and fibroblast entry

Granulation tissue

Collagen-rich remodeling

Causal sequence (schematic)

Slide 30 · Granulation tissue is a transient repair compartment

Proliferating fibroblasts deposit a loose extracellular matrix.

Delicate new capillaries are conspicuous.

Macrophages and other inflammatory cells may be present.

Slide 31 · Angiogenesis supplies the developing repair tissue

Existing vessel

Endothelial sprouting

Capillary tube formation

Pericyte-supported vessel

Mechanistic schematic

Slide 32 · VEGF, FGF-2, and PDGF have complementary roles

VEGF promotes endothelial migration, proliferation, and vascular permeability.

FGF-2 promotes endothelial proliferation and also fibroblast migration.

PDGF helps recruit periendothelial cells and supports vessel maturation.

Slide 33 · Fibroblasts convert inflammation into extracellular matrix

Inflammatory mediators

Fibroblast migration / proliferation

Collagen and fibronectin synthesis

Connective-tissue accumulation

Causal sequence (schematic)

Slide 34 · TGF-β is a central driver of fibrotic repair

Promotes fibroblast migration and proliferation.

Increases collagen and fibronectin synthesis.

Decreases matrix degradation, including by inhibiting metalloproteinases.

Slide 35 · Sustained signaling shifts repair toward fibrosis

Persistent inflammation

Macrophage / lymphocyte mediators

TGF-β and fibroblast activity

Progressive matrix accumulation

Mechanistic schematic

Slide 36 · ECM synthesis and degradation set net scar burden

Matrix synthesis

Matrix degradation

Activated fibroblasts deposit collagen / fibronectin

MMPs cleave ECM components

TGF-β supports deposition

Tissue inhibitors of MMPs restrain proteolysis

Excess synthesis favors fibrosis

Effective remodeling can reduce accumulated ECM

Slide 37 · Myofibroblasts contribute to scar contraction

Some fibroblasts develop actin-containing smooth-muscle-like features.

Contractile activity contributes to progressive shrinkage of scar tissue.

The outcome may be mechanical distortion as well as tissue replacement.

Slide 38 · Granulation tissue matures into a fibrous scar

Early: Vascular, loose ECM

Intermediate: More collagen

Late: Dense, less vascular scar

A maturation sequence, not three separate disease entities

Slide 39 · The histologic appearance evolves with scar maturity

Immature repair shows capillaries and active fibroblasts.

Collagen accumulation increases as granulation tissue matures.

Late scars have fewer visible vessels and more densely packed matrix.

Slide 40 · A scar causes dysfunction through several routes

Parenchymal loss

Architectural distortion

Mechanical rigidity

Vascular or ductal obstruction

Causal sequence (schematic)

Slide 41 · Not all scar burden is proportionate to lost cells

Fibrosis may obstruct circulation even when parenchyma persists.

A stiff fibrous envelope can impair normal organ motion.

The anatomic location of the scar can be as important as its volume.

Slide 42 · Chronic HBV: Fibrosis and hepatocyte regeneration coexist

Fibrous septa around nodules (schematic)

STRUCTURE → FUNCTION

Viral hepatitis

Fibrous septa

Hepatocyte nodules

Slide 43 · Chronic viral hepatitis is portal-centered inflammation with fibrosis

Portal lymphocytic or lymphoplasmacytic infiltrates are characteristic.

Inflammatory cells may extend across the limiting plate.

Lobular inflammation varies in intensity.

Slide 44 · The morphological progression of hepatic fibrosis

Portal / periportal fibrosis

Portoportal bridging fibrosis

Fibrous septa and nodules

Cirrhotic architecture

Causal sequence (schematic)

Slide 45 · Interface activity marks injury at the limiting plate

Inflammatory lymphocytes extend from portal tracts into periportal hepatocytes.

This represents active hepatocyte injury in chronic hepatitis.

Activity and accumulated fibrosis describe different dimensions of disease.

Slide 46 · Bridging fibrosis links portal structures

Portal tract

Fibrous bridge

STRUCTURE → FUNCTION

Portal inflammation

Connecting fibrous bridges

Lobular architectural disruption

Slide 47 · Cirrhosis reorganizes the hepatic vascular map

Dense septa enclose regenerating hepatocyte nodules.

The usual liver architecture is lost.

Distortion of the hepatic circulation changes intrahepatic blood flow.

Slide 48 · Chronic hepatitis activity is not the same as fibrosis stage

Inflammatory activity (grade)

Fibrosis stage

Current necroinflammatory injury

Accumulated connective-tissue distortion

Assessed from hepatocyte injury and inflammation

Assessed from portal, bridging, and cirrhotic fibrosis

May change over time

Records structural disease progression

Slide 49 · HBV may produce distinctive ground-glass hepatocytes

Hepatocyte endoplasmic reticulum accumulates hepatitis B surface antigen.

Cells may acquire a ground-glass cytoplasmic appearance.

HBsAg and core antigen immunostains can support HBV-specific identification.

Slide 50 · Infectious fibrosis is not synonymous with cirrhosis

Cirrhotic architecture

Noncirrhotic periportal fibrosis

Regenerative hepatocyte nodules enclosed by fibrous septa

Fibrous expansion may occur without intervening regenerative nodules

Exemplified by chronic HBV

Exemplified by schistosomal “pipestem” change

Slide 51 · Schistosome eggs provoke the most important host injury

Egg deposition in tissue

Host granulomatous inflammation

Fibroblast-rich healing

Organ-specific scar

Causal sequence (schematic)

Slide 52 · The parasite’s location determines the diseased organ

S. Mansoni and S. Japonicum predominantly affect intestinal and hepatic territories.

S. Haematobium prominently involves the urinary bladder and ureters.

The injury is driven substantially by host responses to deposited eggs.

Slide 53 · Schistosome egg granulomas have recognizable components

An egg can occupy the granuloma center.

Histiocytes, lymphocytes, neutrophils, and eosinophils surround it.

Older eggs may degenerate and calcify.

Slide 54 · Schistosomiasis can shift toward Th2-associated fibrosis

Egg-derived stimulation

Chronic Th2 response

Profibrotic macrophage activation

Hepatic fibrous expansion

Mechanistic schematic

Slide 55 · Hepatic pipestem fibrosis is periportal—not nodular cirrhosis

Expanded portal tracts

STRUCTURE → FUNCTION

Enlarged fibrotic portal tracts

Intervening parenchyma lacks regenerative nodules

Portal vein compromise

Slide 56 · Portal vascular obstruction explains hepatosplenic disease

Periportal fibrosis

Portal venous narrowing / obliteration

Portal hypertension

Splenomegaly, varices, ascites

Causal sequence (schematic)

Slide 57 · Urinary schistosomiasis begins with egg-associated cystitis

S. Haematobium eggs provoke inflammation and granulomas in the bladder wall.

Early mucosal injury may produce erosions and hematuria.

Fibrosis and calcification accumulate in long-standing disease.

Slide 58 · Fibrotic urinary tract injury becomes obstructive

Patent lumen

Narrowed lumen

STRUCTURE → FUNCTION

Egg-associated inflammation

Ureteral-wall fibrosis

Urinary outflow obstruction

Slide 59 · Long-standing urinary schistosomiasis has additional sequelae

Ureteral obstruction can cause hydronephrosis and chronic pyelonephritis.

Calcified egg granulomas can produce a “sandy” or calcified bladder wall.

Urinary schistosomiasis is associated with squamous cell carcinoma of the bladder.

Slide 60 · HBV versus schistosomiasis: Different liver architecture

Chronic HBV liver disease

Hepatic schistosomiasis

Portal inflammation and hepatocyte injury

Egg granulomas and portal-predominant fibrosis

Bridging fibrosis; cirrhotic nodules may form

“Pipestem” fibrosis without intervening nodules

Architectural distortion with altered blood flow

Portal vein loss / obstruction and portal hypertension

Slide 61 · Tuberculosis can produce a fibrosing pericardial lesion

Constrictive fibrous pericarditis as a scarring sequel.

Tuberculous pericarditis can exhibit caseation.

Chronic organization may leave a thickened fibrous or fibrocalcific envelope.

Slide 62 · Constrictive pericarditis: A mechanical consequence of scar

Fibrous shell

Schematic pericardial encasement

STRUCTURE → FUNCTION

Inflamed pericardium

Dense encasing scar

Limited diastolic expansion

Slide 63 · A rigid pericardium impairs cardiac performance

Fibrous encasement

Restricted diastolic filling

Reduced reserve of cardiac output

Venous congestion

Causal sequence (schematic)

Slide 64 · Constrictive pericarditis has a distinctive clinical logic

Elevated jugular venous pressure and peripheral edema reflect venous congestion.

Cardiac output may be limited, particularly during increased demand.

Pericardiectomy removes the restraining fibrous envelope in suitable cases.

Slide 65 · How pathologists frame suspected infection-associated scarring

Observed tissue feature

Pathologic question

Mononuclear infiltrate

Is inflammation ongoing?

Granuloma and giant cells

Is a persistent antigen/organism driving it?

Collagen-rich septa

What architecture is lost or separated?

Obliterated vessel / duct

How does fibrosis explain organ dysfunction?

Slide 66 · Etiologic confirmation requires more than fibrosis

Tissue reaction patterns are useful but not organism-specific.

Use clinical context and microbiologic / pathologic testing where appropriate.

Granulomas warrant assessment for mycobacterial and fungal causes, among others.

Slide 67 · Case 1 — fibrotic liver with regenerative nodules

A patient with chronic HBV has portal inflammation, bridging fibrosis, and hepatocyte nodules surrounded by dense septa.

INTERPRETIVE QUESTION

Question: What architectural diagnosis follows, and why may hepatic blood flow change?

Slide 68 · Case 2 — portal fibrosis without regenerative nodules

A patient from a schistosomiasis-endemic setting has portal hypertension and markedly expanded fibrotic portal tracts.

INTERPRETIVE QUESTION

Question: What morphologic feature distinguishes this pattern from cirrhosis?

Slide 69 · Case 3 — a scarred, poorly compliant pericardium

A patient with a prior tuberculous pericardial process has venous congestion and a rigid, fibrous pericardial envelope.

INTERPRETIVE QUESTION

Question: What is the mechanical basis of impaired cardiac output?

Slide 70 · Case 4 — bladder scarring with calcified eggs

A patient has hematuria and a thickened bladder wall containing granulomas and calcified helminth eggs.

INTERPRETIVE QUESTION

Question: Which infection fits, and what obstructive complication may develop?

Slide 71 · Four mechanisms link infection to chronic dysfunction

Mechanism

Illustrative outcome

Repeated parenchymal injury

Hepatocyte loss during chronic hepatitis

Septal fibrosis and regeneration

Cirrhotic hepatic architecture

Perivascular / periductal scarring

Portal hypertension or urinary obstruction

Fibrous encasement

Restricted cardiac diastolic filling

Slide 72 · Consolidated pathologic principles

Chronic infection may produce inflammation, injury, and repair simultaneously.

Profibrotic mediators and fibroblasts translate persistent injury into ECM deposition.

The functional result depends on which normal architecture the scar replaces, encloses, or obstructs.

Slide 73 · Primary Robbins sections used in this lecture

Chapter 8, Infectious Diseases: “Chronic Inflammation and Scarring,” pp. 312–313.

Chapter 3, Inflammation and Repair: “Chronic Inflammation” and “Tissue Repair,” pp. 86–97.

Chapter 8, Schistosomiasis, pp. 363–365; Chapter 18, Viral Hepatitis, pp. 760–762.

Chapter 12, The Heart: pericardial inflammation and constriction, pp. 526–527.