Objectives

This lecture provides an understanding of

Cells involved, etiologies, cellular

constituents, general histologic features, of

chronic inflammation

Granulomatous inflammation

Role of lymphatics in the inflammation

Learning outcomes

At the end of the lecture ,student will be able to

Identify and distinguish the cells involved in chronic inflammation

List various causes of chronic inflammation

Describe the morphological features of chronic inflammation

Define chronic granulomatous inflammation

List examples of diseases with granulomatous inflammation

Describe the morphology of granulomatous inflammation

Describe the role of lymphatics in the inflammation

Tissue response to an injury

Definition of chronic inflammation

an inflammatory response of prolonged duration (weeks – months - years)

provoked by the persistence of the causative stimulus

simultaneous presence of active inflammation, tissue destruction and repair

DEFINITION

Inflammation of prolonged duration

( weeks or months) in which

- active inflammation

- tissue destruction and

- attempts at healing

proceed simultaneously

Chronic Inflammation arrives in 3 ways:

1.May follow acute inflammation

e.g pneumonia -> chronic lung abscess

2. Repeated bouts of acute inflammⁿ

e.g cholecystitis , pyelonephritis

3. Begin insiduously as a low grade smouldering reponse

Chronic inflammation arises in the following settings: (CAUSES)

Persistent infections

Immune-mediated inflammatory

diseases

Prolonged exposure to non-degradable

but potentially toxic substances

Persistent infections by microbes

that are difficult to eradicate

Eg: mycobacteria,

Treponema pallidum (causative organism

of syphilis)

certain viruses, fungi and parasites

Immune-mediated inflammatory diseases

autoimmune diseases

(under certain conditions, immune reactions

develop against the individual's own tissues)

Eg:rheumatoid arthritis, multiple sclerosis

allergic diseaseshypersensitivity reaction that are caused by excessive

and inappropriate activation of the immune system)

Eg:bronchial asthma

Prolonged exposure to toxic substances

(non-degradable)– Exogenous (asbestos, silicon)

– Endogenous (chronically elevated plasma lipid components which

may contribute to atherosclerosis)

Cells of Chronic Inflammation

macrophages

lymphocytes

plasma cells

eosinophils

neutrophils

Maturation of Mononuclear Phagocytes

Macrophage

• Mononuclear Phagocyte System (MPS)

Circulating blood monocytes →Tissue macrophages

↓

Kupffer cells (liver)

Sinus Histiocytes (spleen)

Microglia (CNS)

Alveolar Macrophages (lung)

During chronic inflammation

macrophages serve to eliminate

injurious agents and initiate repair

however, they are as well responsible

for much of the tissue injury that

occurs

Macrophage

IFN-g

Activated T cell or NK cell

Tissue macrophage

Activated macrophage

Non Immune activation:Endotoxins, fibronectin, chemical mediators

Tissue injuryToxic oxygen metabolitesMetallo-proteasesCoagulation factorsAA metabolites and NO

Fibrosis (Scaring)Growth factors involved in fibroblast proliferation(PDGF,TGFb,FGF)Angiogenesis factors(FGF,VEGF)Collagen deposition (IL-13 and TGFb)

Macrophage:component of MPStransformed from monocytes

prime cell of chr: inflammⁿActivated by lymphokines bact: endotoxin Activated macrophages

secrete:EnzymesO2 metabolites , cytokinesgrowth factorsNO , PAF,IFN α resultingt/s destructionneovascularisation fibrosis

In chronic inflammation macrophage accumulation persists by

different mechanisms

Continued recruitment of monocytes

from the circulation

Local proliferation

Prolonged survival and immobilization

Lymphocytes:

Naive lymphocytes encounter antigen-presenting cells

and become antigen-specific lymphocytes

Activated T lymphocytes

Regulate macrophage activation and recruitment by secreting specific mediators cytokines (lymphokines) (IFN-γ)

Modulate anti-body production and cell-mediated cytotoxicity and maintain immunologic memory

Plasma cells:

develop from activated B lymphocytes

produce antibody directed either against persistent antigen in the inflammatory site or against altered tissue components

Mast Cells:

- Widely distributed in connective tissues and

participate in both acute and persistent inflammatory reactions

- Binds the Fc portion of the IgE antibody

Cells of Chronic Inflammation

Eosinophils:

- parasitic infections

- Mediated by IgE

- Eotaxin – a chemokine that has the ability to prime eosinophils for chemotaxis

- have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells

Chronic inflammation is characterized by

Infiltration with mononuclear cells(including macrophages, lymphocytes, and plasma cells)

indicates persistent reaction to injury

Tissue destruction(largely induced by the products of the inflammatory cells)

Repair (Healing)(involving new vessel proliferation (angiogenesis) and fibrosis)

Attempt to replace lost tissue

Chronic inflammation in the lungshowing all three characteristic histologic features: (1)collection of chronic inflammatory cells (2)destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium(3) replacement by connective tissue (fibrosis)

Chronic ulcer such as

chronic peptic ulcer of the stomach with

breach of the mucosa, a base lined by

granulation tissue and with fibrous tissue

extending through the muscle layers of the

wall

Chronic abscess cavity for example

osteomyelitis, empyema thoraccis

Thickening of the wall of a hollow viscus by

fibrous tissue in the presence of a chronic

inflammatory cell infiltrate, for example

Crohn's disease, chronic cholecystitis

Fibrosis

The most prominent feature of the chronic

inflammatory reaction when most of the

chronic inflammatory cell infiltrate has

subsided. This is commonly seen in

chronic cholecystitis

'hour-glass contracture' of the stomach, lead to acquired

pyloric stenosis

the strictures that characterise Crohn's diseas

Gallbladder showing chronic cholecystitisThe wall is greatly thickened by fibrous tissue

Chronic inflammation in the wall of a gallbladder that has experienced previous episodes of acute cholecystitis Aggregates of lymphocytes and ingrowing fibroblasts

Chronic peptic ulcer of the stomachContinuing tissue destruction and repair cause replacement of the gastric wall muscle layers by fibrous tissueAs the fibrous tissue contractspermanent distortion of the gastric shape may result

A distinctive pattern of chronic inflammation

characterized by focus of chronic

inflammation consisting of a microscopic

aggregation of macrophages that are

transformed into epithelium-like cells,

surrounded by a collar of mononuclear

leukocytes, principally lymphocytes and

occasionally plasma cells fibroblasts

CHRONIC GRANULOMATOUS INFLAMMATION

CHRONIC GRANULOMATOUS INFLAMMATION

A distinctive pattern of chronic

inflammation characterised by

granulomas which are small nodular

collections in which the predominant

cell is the activated macrophage with

epithelial like (epitheloid) appearance

with abundant pink cytoplasm

Granuloma:

A granuloma is a focus of chronic

inflammation consisting of

a microscopic aggregation of macrophages

that are transformed into epithelium-like

cells (epitheloid cells) surrounded by a

collar of mononuclear leukocytes,

principally lymphocytes and occasionally

plasma cells

MORPHOLOGY

Epitheloid cell:(Activated

Macrophage)

-pale pink granular cytoplasm

-indistinct cell boundary

-oval or elongated nucleus +/- folding of

nuclear membrane

-may fuse to form giant cells

Giant cells:

- 40 to 50 µ in diam

- abundant cytoplasm

Langhans' type - 20 or more nuclei in

periphery ( horse shoe pattern)

Foreign body type - nuclei scattered in

cytoplasm

Caseous necrosis

Grossly - this has a granular, cheesy

appearance

Microscopically - appears as amorphous,

structureless, granular debris, with

complete loss of cellular details

central caseous necrosis

Epitheloid Cells

Typical tuberculous granuloma showing an area of central necrosis surrounded bymultiple Langhans-type giant cells, epithelioid cells, and lymphocytes.

central necrosis

Langhans-type giant cells

lymphocytes

Granuloma with caseous necrosis

The lung of a patient with miliary tuberculosis1 to 2 mm granulomas are scattered around like millet seeds (millet is a type of cereal grain)With poor immune responseextensive spread of infection with the production of a "miliary" pattern of granulomas

Scattered granulomas

Types of granuloma:

1. Foreign body granuloma

2. Immune granuloma

(a) indigestible particles or organisms

(b) T cell mediated Immune Response

3. Toxic granuloma – due to silicon, beryllium

In tuberculosis, granuloma is

referred

to as tubercle,

• Hard tubercle

• Soft tubercle – characterized by presence

of central caseous necrosis; caseation

necrosis is rare in other granulomatous

disease

Examples of Diseases with Granulomatous Inflammation

Tuberculosis

Leprosy

Syphillis

Cat – scrath disease

Sarcoidosis

Crohn disease (inflammatory bowel

disease)

Examples of Chronic Granulomatous Inflammation:

Bacterial

TB, leprosy, syphilis,

Parasitic

Schistosomiasis

FungalCryptococcosis,Histoplasmosis,Blastomycosis,

Unknown

Sarcoidosis

Common Causes of Epithelioid Cell Granulomas.Disease Causes

Immunologic response 

  Tuberculosis Mycobacterium tuberculosis 

  Leprosy (tuberculoid type) Mycobacterium leprae 

  Histoplasmosis Histoplasma capsulatum 

  Coccidioidomycosis Coccidioides immitis 

  Q fever Coxiella burnetii (rickettsial

organism) 

  Brucellosis Brucella species 

  Syphilis Treponema pallidum   

  Sarcoidosis2

 

Unknown

  Crohn's disease2

 

Unknown

  Berylliosis3

 

Beryllium (? +protein)

Nonimmunologic response 

  Foreign body (eg, in intravenous

drug abuse)

Talc, fibers (? +protein)

COMPARISON OF ACUTE AND CHRONIC INFLAMMATION

FEATURE ACUTE

INFLAMMATION

CHRONIC

INFLAMMATION

Onset &duration Immediate &

Transient (few

days)

Delayed &

weeks,months, years

Pathogenesis Microbial pathogens,

trauma, burns

Persistent acute inflammation,

foreign bodies (e.g., silicone,

glass), autoimmune disease,

certain types of infection (e.g.,

tuberculosis, leprosy)

FEATURE ACUTE INFLAMMATION CHRONICINFLAMMATION

Primary cells NeutrophilsMonocytes/macrophages cells), B and T lymphocytes plasma cells, fibroblasts

Necrosis Present Less prominent

Scar tissue Absent Present

Outcome Complete resolution, Scar tissue formation

disability, amyloidosis

progression to

chronic inflammation

abscess formation

COMPARISON OF ACUTE AND CHRONIC INFLAMMATION

Differences between Acute and Chronic Inflammation

  Acute Chronic

Duration Short (days) Long (weeks to months)

Onset Acute Insidious

Specificity Nonspecific Specific (where immune response is activated)

Inflammatory cells Neutrophils, macrophages Lymphocytes, plasma cells, macrophages,

fibroblasts

Vascular changes Active vasodilation, increased permeability New vessel formation (granulation tissue)

Fluid exudation and edema + –

Cardinal clinical signs

(redness, heat, swelling,

pain)

+ –

Tissue necrosis – (Usually)

+ (Suppurative and necrotizing inflammation)

+ (ongoing)

Fibrosis (collagen

deposition)

– +

Operative host responses Plasma factors: complement, immunoglobulins, properdin,

etc; neutrophils, nonimmune phagocytosis

Immune response, phagocytosis, repair

Systemic manifestations Fever, often high Low–grade fever, weight loss, anemia

Changes in peripheral blood Neutrophil leukocytosis; lymphocytosis (in viral infections) Frequently none; variable leukocyte changes,

increased plasma immunoglobulin

In acute inflammation the lymphatic channels

become dilated & drain away the oedema fluid of

the inflammatory exudate

This drainage tends to

limit the extent of oedema in the tissues

carry large molecules and some particulate matter

&

antigens are carried to the regional lymph nodes

for recognition by lymphocytes