patoloji-ders-notlari
Title
Serdar Balcı
Chronic Inflammation
Serdar BALCI, MD
Robbins Basic Pathology
Robbins Basic Pathology
**collection of chronic inflammatory cells **
Chronic inflammation in the lung
destruction of parenchyma
**neutrophils fill the alveolar spaces **
acute inflammation of the lung
acute bronchopneumonia
blood vessels are congested
Robbins Basic Pathology
Chronic Inflammation
- inflammation of prolonged duration (weeks to years)
- continuing inflammation
- tissue injury
- healing
- often by fibrosis
proceed simultaneously
- Infiltration with mononuclear cells
- macrophages, lymphocytes, and plasma cells
- Tissue destruction
- induced by the products of the inflammatory cells
- Repair
- new vessel proliferation (angiogenesis) and fibrosis
Chronic inflammation may arise: 1) From acute inflammation
- acute response cannot be resolved
- persistence of the injurious agent
- interference with the normal process of healing
Chronic inflammation may arise: 2) Persistent infections by microbes that are difficult to eradicate
Mycobacterium tuberculosis
Treponema pallidum
syphilis
certain viruses and fungi
tend to establish persistent infections
T lymphocyte–mediated immune response
delayed-type hypersensitivity
Chronic inflammation may arise: 3) Immune-mediated inflammatory diseases (hypersensitivity diseases)
- excessive and inappropriate activation of the immune system
- Autoimmune Diseases
- rheumatoid arthritis, inflammatory bowel disease, and psoriasis
- Allergic Diseases
- bronchial asthma
Chronic inflammation may arise: 4) Prolonged exposure to potentially toxic agents
nondegradable exogenous materials
inhaled particulate silica
endogenous agents
cholesterol crystals, atherosclerosis
Are these chronic inflammatory diseases? We do not know the definite answer, yet Jury is still out
- Neurodegenerative disorders
- Alzheimer disease
- Atherosclerosis
- Metabolic syndrome
- Type 2 diabetes
- Some forms of cancer
Mixed acute and chronic inflammation can be observed in immune mediated diseases
repeated acute phases
exacerbation of underlying chronic inflammation
Many forms of chronic inflammation may continue to show extensive neutrophilic infiltrates
- persistent microbes or necrotic cells
- **mediators elaborated by macrophages. **
- Such inflammatory lesions are designated as follows:
- “acute on chronic” osteomyelitis
- Active chronic gastritis
Some examples for chronic inflammation
Chronic inflammation in the wall of a gallbladder that has experienced previous episodes of acute cholecystitis
Gallbladder showing chronic cholecystitis
Chronic peptic ulcer of the stomach
Pathology - The Big Picture
**Pulmonary fibrosis (idiopathic) **
**Transplant rejection: kidney **
**Xanthogranulomatous inflammation and lipogranuloma **
**Pilonidal sinus **
Inflammation
Stephenson, Timothy J., Underwood’s Pathology: A Clinical Approach, 9, 165-182
Chronic Inflammatory Cells and Mediators
Macrophages
Lymphocytes
Eosinophils
Mast cells
Inflammation
Stephenson, Timothy J., Underwood’s Pathology: A Clinical Approach, 9, 165-182
Robbins and Cotran Pathologic Basis of Disease
Macrophages
the dominant cells of chronic inflammation
derived from circulating blood monocytes after their emigration from the bloodstream
**normally diffusely scattered in most connective tissues and organs **
Liver → Kupffer cells
spleen and lymph nodes sinus → histiocytes
central nervous system → microglial cells
lungs → alveolar macrophages
mononuclear phagocyte system
reticuloendothelial system
adhesion molecules and chemokines
Migrate within 24 to 48 hours after the onset of acute inflammation
transformation into macrophages
larger
longer lifespan
greater capacity for phagocytosis
circulate in the blood for only about a day
Robbins and Cotran’s Pathological Basis of Diseases
Macrophage Activation
Robbins Basic Pathology
Classical macrophage activation
- induced by microbial products
- endotoxin
- T cell–derived signals
- cytokine IFN-γ
- foreign substances
- crystals, particulate matter
- produce lysosomal enzymes, NO, and ROS
- enhance their ability to kill ingested organisms
- secrete cytokines
- stimulate inflammation
Alternative macrophage activation
- induced by IL-4 and IL-13
- produced by T lymphocytes, mast cells and eosinophils
- not actively microbicidal
- principal role is in tissue repair
- secrete growth factors
- angiogenesis
- activate fibroblasts
- stimulate collagen synthesis
Robbins and Cotran’s Pathological Basis of Diseases
Macrophages
- central to the initiation and propagation of all inflammatory reactions
- like neutrophils, ingest and eliminate microbes and dead tissues
- initiate the process of tissue repair
- involved in scar formation and fibrosis
- secrete mediators of inflammation
- cytokines (TNF, IL-1, chemokines)
- eicosanoids
- most important phagocytes in the T cell-mediated arm of adaptive
immune responses
- display antigens to T lymphocytes
- respond to signals from T cells
After inflammation
the initiating stimulus is eliminated
macrophages die
go into lymphatics
In chronic inflammatory sites
macrophage accumulation persists
continued recruitment from the blood and local proliferation
IFN-γ induce macrophages to fuse into large, multinucleate giant cells
RUBINS PATHOLOGY Clinicopathologic Foundations of Medicine
Lymphocytes
- any specific immune stimulus
- infections
- non–immune-mediated inflammation
- due to ischemic necrosis or trauma
- autoimmune and other chronic inflammatory diseases
- part of the adaptive immune response in infections and immunologic diseases
T helper cells
- T H 1 cells produce IFN-γ
- activates macrophages in the classical pathway.
- T H 2 cells secrete IL-4, IL-5, and IL-13
- recruit and activate eosinophils
- Activate macrophages for the alternative pathway
- T H 17 cells secrete IL-17 and other cytokines
- induce the secretion of chemokines
- responsible for recruiting neutrophils and monocytes
- T H 1 and T H 17
- bacteria, viruses, autoimmune diseases
- T H 2
- helminthic parasites
- allergic inflammation
Bidirectional Interaction
Inflammation
Stephenson, Timothy J., Underwood’s Pathology: A Clinical Approach, 9, 165-182
Bidirectional Interaction
Robbins Basic Pathology
Bidirectional Interaction
Robbins and Cotran’s Pathological Basis of Diseases
Activated B lymphocytes and antibody-producing plasma cells
- Often present at sites of chronic inflammation
- Antibodies against
- persistent foreign antigen
- self antigens in the inflammatory site or against altered tissue components
Eosinophils
- **Found in **
- around parasitic infections
- immune reactions mediated by IgE, allergies
- Driven by
- adhesion molecules similar to neutrophils
- specific chemokines (eotaxin) derived from leukocytes and epithelial cells
- Eosinophil granules contain major basic protein
- highly charged cationic protein
- toxic to parasites
- also causes epithelial cell necrosis
Robbins and Cotran’s Pathological Basis of Diseases
Mast cells
- sentinel cells
- widely distributed in connective tissues throughout the body
- participate in both acute and chronic inflammatory responses
- Atopic persons (prone to allergic reactions)
- have IgE antibody on surface specific for certain environmental antigens
- when these antigens are encountered, mast cells release histamines and AA metabolites
- early vascular changes of acute inflammation
- allergic reactions
- anaphylactic shock
**Cells in chronic inflammation **
Granulomatous inflammation
- characterized by
- aggregates of activated macrophages
- scattered lymphocytes
- 1) persistent T-cell responses to certain microbes
- Mycobacterium tuberculosis, T. pallidum, fungi
- cytokines are responsible for chronic macrophage activation
- Tuberculosis is the prototype of a granulomatous disease
- should always be excluded as the cause when granulomas are identified
- 2) immune-mediated inflammatory diseases
- Crohn disease
- inflammatory bowel disease
- 3) sarcoidosis
RUBINS PATHOLOGY Clinicopathologic Foundations of Medicine
Robbins and Cotran’s Pathological Basis of Diseases
Activated macrophages in granulomas
pink, granular cytoplasm
indistinct cell boundaries
epithelioid cells
Aggregates of epithelioid macrophages surrounded by lymphocytes
Frequently multinucleate giant cells 40 to 50 μm in diameter
from the fusion of multiple activated macrophages
Robbins and Cotran’s Pathological Basis of Diseases
Activated macrophages in granulomas
pink, granular cytoplasm
indistinct cell boundaries
epithelioid cells
Pathology - The Big Picture
Robbins Basic Pathology
a combination of hypoxia and free radical injury leads to a central zone of necrosis
eosinophilic amorphous, structureless, granular debris, with complete loss of cellular details
Robbins Basic Pathology
**granular, cheesy appearance and is therefore called caseous necrosis **
Older and healing granulomas have a rim of fibroblasts and connective tissue
Autopsy Pathology: A Manual and Atlas
Robbins Basic Pathology
RUBINS PATHOLOGY Clinicopathologic Foundations of Medicine
Mycobacterium tuberculosis acid-fast Ziehl-Neelsen stain; Magnified 1000X.
http://phil.cdc.gov/
RUBINS PATHOLOGY Clinicopathologic Foundations of Medicine
**Foreign body reaction **
**Foreign body reaction **
RUBINS PATHOLOGY Clinicopathologic Foundations of Medicine
The granulomas associated with Crohn disease, sarcoidosis, and foreign body reactions
Do not have necrotic centers
Noncaseating __ __
Robbins and Cotran’s Pathological Basis of Diseases
“Asistanlardan biri, Fransızca anlamadığıma hükmederek;”Tumeur blanche’ların ekseriya bol akıntılarla ciğer veremi tevlit edebileceğini anlatıyor. Mithat Bey ona susmasını ihtar etti.“
Peyami Safa - Dokuzuncu Hariciye Koğuşu
Systemic effects of inflammation acute-phase reaction
mediated by the cytokines TNF, IL-1, and IL-6
Fever, elevation of body temperature
- pyrogens stimulate prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus
- Bacterial products, lipopolysaccharide (exogenous pyrogens)
- stimulate leukocytes
- release cytokines (IL-1, TNF endogenous pyrogens)
- increase the levels of cyclooxygenases
- convert AA into prostaglandins
- PGE 2 act on hypothalamus
- stimulate the production of neurotransmitters
- reset the temperature set point at a higher level
- NSAIDs (aspirin), reduce fever by inhibiting cyclooxygenase
Elevated plasma levels of acute-phase proteins
Mostly synthesized in the liver, stimulated by cytokines (IL-6)
In acute inflammation, concentrations increase several hundred-fold
C-reactive protein (CRP)
Fibrinogen
Serum amyloid A (SAA) protein
Acute-phase proteins
- CRP and SAA
- bind to microbial cell walls
- act as opsonins
- fix complement
- promote the elimination of the microbes
- Fibrinogen
- binds to erythrocytes
- form stacks (rouleaux)
- sediment more rapidly at unit gravity than individual erythrocytes
- erythrocyte sedimentation rate (ESR)
- Serial measurements of ESR and CRP are used to assess therapeutic responses in patients with inflammatory disorders such as rheumatoid arthritis
Leukocytosis
- initially because of accelerated release of cells from the bone
marrow
- influence of cytokines, TNF and IL-1
- Both mature and immature neutrophils may be seen in the blood
- shift to the left
- Prolonged infection
- stimulates production of colony-stimulating factors (CSFs)
- increase the bone marrow output of leukocytes
- compensating for the consumption of these cells in the inflammatory reaction
- Most bacterial infections → neutrophilia
- Viral infections → lymphocytosis
- Bronchial asthma, hay fever, and parasite infestations → eosinophilia
- typhoid fever, some viruses, rickettsiae, certain protozoa → leukopenia
Other manifestations of the acute-phase response
- increased heart rate and blood pressure
- decreased sweating
- rigors (shivering)
- chills (perception of being cold as the hypothalamus resets the body temperature)
- anorexia
- somnolence
- malaise, probably secondary to the actions of cytokines on brain cells.
- TNF
- disseminated intravascular coagulation (DIC)
- metabolic disturbances including acidosis
- hypotensive shock
