acute and chronic inflammation
TRANSCRIPT
Acute and Chronic Inflammation
Referrence Chapter 2, “Acute and Chronic
Inflammation” in Robbins’ Basic Pathology, pages 31-57
Introduction Inflammation is a defensive host
response to foreign invaders and necrotic tissue.
Can be acute or chronic.
Acute inflammation
Acute inflammation Immediate and early response to
tissue injury (physical, chemical, microbiologic, etc.)
Acute inflammation has two major components : Vascular changes Cellular events
Vascular change
Vascular change The main vascular reactions of acute
inflammation are increased blood flow followed by vasodilation and increased vascular permeability: warmth and redness Opens microvascular beds and protein-
rich fluid moves into extravascular tissues Migration of leukocytes (principally neutrophils)
Increased vascular permeability This will leads to the movement of
protein-rich fluid and blood cells into the extravascular tissue. The resulting protein-rich
accumulation is called an exudate. Increases interstitial osmotic pressure
contributing to edema.
Vascular leakage several mechanisms may contribute
to increased vascular permeablity: Endothelial cell contraction that leading
to intracellular gaps of venules This occur after binding of histamines and
bradykinins, and many other mediators and is usually short-lived (15 – 30 min.)
Vascular leakage
Cytokine mediators (TNF, IL-1) induce endothelial cell junction retraction through cytoskeleton reorganization
This reaction may take 4 – 6 hrs to develop ,and lasting for 24 hrs or more
Vascular leakage Endothelial injuries result in vascular
leakage by causing direct endothelial cell necrosis, detachment making them leaky until they are repaired or may cause delayed damage as in thermal, certain bacterial toxins or Ultraviolet injury.
Vascular leakage Certain mediators such as vascular
endothelial growth factor (VEGF) may cause increased transcytosis via intracellular vesicles which travel from the luminal to basement membrane surface of the endothelial cell
All or any combination of these events may occur in response to a given stimulus
Leukocyte cellular events
Leukocyte cellular events Leukocytes leave the vascular lumen to
the extravascular space through the following sequence of events: Margination and rolling along the vessel wall Firm adhesion and transmigration between
endothelial cells Chemotaxis and activation
Margination and Rolling With increased vascular permeability, fluid
leaves the vessel causing leukocytes to settle-out of the central flow column and “marginate” along the endothelial surface
Endothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium until it eventually comes to a stop as mutual adhesion reaches a peak
Margination and Rolling Early rolling adhesion mediated by
selectin family of adhesion molecules: E-selectin (on endothelium cell) P-selectin (present on platelets,
endothelium) L-selectin (on the surface of most
leukocytes)
Adhesion The rolling leukocytes are able to sense
change on the endothelium that initiate the next step in the reaction of leukocytes, which is firm adhesion to endothelial surface
Occur as leukocytes adhere to the endothelial surface and is mediated by the interaction of integrins on leukocytes binding to IG-family adhesion proteins on the endothelium.
Transmigration (diapedesis)
Is the movement of leukocyte across the endothelial surface
Occurs after firm adhesion and mediated by palatelete endothelial cell adhesion molecules-1 (PECAM –1)
on both leukocyte and endothelium
Chemotaxis Leukocytes follow chemical gradient to
site of injury this process called (chemotaxis)
Chemotactic factors for neutrophils, produced at the site of injury, include: Bacterial products Components of complement system especially (C5a) Cytokines.
Phagocytosis Phagocytosis is the ingestion of
particulate material by phagocytic cell
neutrophils and monocytes-macrophages are the most important phagocytic cells
Phagocytosis consists of three steps: Recognition and attachment of the
particle Engulfment (form phagocytic vacuole) Killing and degradation of the
ingested materials.
Defects of leukocyte function Defects of leukocyte adhesion:
Leukocyte adhesion deficiency type I : is associated with recurrent bacterial
infections. Leukocyte adhesion deficiency type 2 : is associated with recurrent bacterial
infections and result from mutations in the gene that required for the synthesis of sialyl-lewis X on neutrophils.
Defects of leukocyte function Defects of
chemotaxis/phagocytosis: Microtubule assembly defect leads to
impaired locomotion and lysosomal degranulation (Chediak-Higashi Syndrome)
Possible outcomes of acute inflammation
Possible outcomes of acute inflammation Complete resolution of tissue structure
and function: When the injury is limited or short-lived. There has been no or little tissue damage When the injured tissue is capable of regeneration
Scarring (fibrosis): When inflammation occur in tissues that do not
regenerate The injured tissue is filled with connective tissue
Outcomes (cont’d) Abscess formation occurs with
some bacterial or fungal infections Progression to chronic
inflammation.
Chronic inflammation
Chronic inflammation Is inflammation of prolonged duration
(week to years) in which continuing inflammation, tissue injury, and healing, often by fibrosis, proceed simultaneously.
Chronic inflammation Is characterized by a different set of
reactions: Lymphocyte, macrophage, plasma cell
(mononuclear cell) infiltration Tissue destruction by inflammatory cells Repair with fibrosis and angiogenesis
(new vessel formation)
Chronic inflammation may arise in the following setting : Persistent injury or infection (ulcer, TB) Prolonged toxic agent exposure (silica) Autoimmune disease states (RA, SLE)
Chronic inflammatory cells and mediators
Chronic inflammatory cells and mediators Macrophages
The dominant cells. Scattered all over (Kupffer cells,
sinus histiocytes, alveolar macrophages, etc.
Derived from circulating blood monocytes and reach site of injury within 24 – 48 hrs and transform to macrophages.
Chronic inflammatory cells and mediators Two majors pathways of macrophage
activation: Classical macrophage activation: induced byT cell-derived cytokines, endotoxins, and other
products of inflammation Alternative macrophage activation: induced by cytokines produced by T lymphocytes and other cell
including mast cell and eosinophils
Chronic inflammatory cells and mediators Macrophages have several roles in host
defense and inflammatory reaction: Ingest and eliminate microbes and dead
tissue. Initiate the process of tissue repair. Secrete mediators of inflammation such
as cytokines.
Chronic inflammatory cells and mediators Lymphocytes (T - B )
Antigen-activated (via macrophages and dendritic cells)
Lymphocytes and macrophages interact in a bidirectional way and these interaction
play an important role in propagating chronic inflammation lymphocyte release macrophage-activating cytokines (in turn, macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed)
Chronic inflammatory cells and mediators Eosinophils
Found especially at sites of parasitic infections, and as part of immune reaction mediated by IgE
Typically associated with allergies.
Granulomatous Inflammation
Granulomatous Inflammation Is a distinctive pattern of chronic
inflammation characterized by aggregates of activated macrophages and scattered lymphocytes.
Granulomatous Inflammation can form under three setting : Persistance T-cell response to certain
microbes (such as TB) In some immune mediated inflammatory
diseases (Crohn disease) In sarcoidosis disease in response to
relatively inert foreign bodies(suture or splinter)
Systemic effects
Systemic effects Fever
The most prominent manifestation of acute-phase response.
Fever is produced in response to pyrogens which stimulate prostoglandine synthesis.
PGE stimulate the production of neurotransmitters to reset the temperature at a higher level.
Systemic effects (cont’d) Leukocytosis
Is a common feature of inflammatory reaction, espicially those induced by bacterial infection
Elevated white blood cell count. Other manifestations include:
Increased heart rate and blood pressure. Decreased sweating. Sepsis in severe bacterial infection.
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