Path: Chronic Inflammation and Systemic Effects of Inflammation

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Unit 1, Week 4

Macrophages (6)

Evolutionarily oldest mediator of innate immunity
Component of mononuclear phagocyte system: originates in bone marrow
Begin as monocytes: circulate in blood, leave through venules
Activated (to macrophages) in various CTs
Largest of leukocytes
Indented, but not 'lobed' nucleus
Monocytes circulate ~14 hrs then leaves circulation by diapedesis; macrophages (tissue) live months to years

Macrophage: Signals for Wound Debridement, Removal of injured tissue and debris (3)

Phagocytosis
Collagenase
Elastase

Macrophage: Signals for Antimicrobial activity

Nitric acid
ROS

Macrophage: Signals for Chemotaxis and proliferation of fibroblasts and keratinocytes (5)

PDGF
TGF-beta
TNF
IL-1
KGF-7

Macrophage: Signals for Angiogenesis (3)

VEGF
FGF-2
PDGF

Macrophage: Signals for Deposition and remodeling of ECM (7)

TGF-beta
PDGF
TNF
OPN
IL-1
Collagenase
MMPs

Classic Activation of Macrophages (4)

Undergo differentiation in CT
Up-regulation of MHCII and CD80/CD86 (B7)
2 signals: IFN-gamma and PAMPs (recognized by PRRs)
Microbicidal; involved in potentially harmful inflammation

Alternative Activation of Macrophages (3)

Induced by other cytokines and in response to helminths
Important in tissue repair and resolution of inflammation
May play a role in defense against helminthic parasites

Leukocyte Receptors and Responses (2-2, 2)

G protein-coupled receptors: cytoskeletal changes, signal transduction
-increased integrin activity --> adhesion to endothelium
-chemotaxis --> migration into tissues
Toll-like receptor: production of mediators --> amplification of inflammatory reaction; production of reactive oxygen species (ROS) and lysosomal enzymes --> killing of microbes
Cytokine receptor: production of ROS and lysosomal enzymes --> killing of microbes
Phagocytic receptor: production of ROS and lysosomal enzymes, phagocytosis of microbe into phagosome
-killing of microbes

G protein-coupled receptors

ADD ^^^ plus what they bind for all receptors

Macrophages: Dynamic membrane specializations - actin-based motility (3)

Cell crawling/membrane ruffling
Diapedesis (extravasation): occurs in post-capillary venules
Phagocytosis

Acute vs Chronic Inflammation (1-7, 1-5)

Acute:
-rapid onset
-short duration (hours-days)
-characterized by:
>vascular dilation
>edema
>emigration of leukocytes (mostly neutrophils)
-associated lesion = abscess
Chronic:
-follow acute or begin insidiously
-longer duration (weeks or months)
-cells involved: lymphocytes, macrophages, plasma cells
-tissue destruction and attempted tissue repair
-associated lesion = granuloma

Causes of Chronic Inflammation (3)

Persistent infections: Mycobacteria and various viruses, fungi, and parasites
Immune-mediated inflammatory diseases: autoimmune disease, unregulated immune response against microbes, asthma
Prolonged exposure to potentially toxic agents, either exogenous or endogenous: silica

CI: Morphologic Features (3-2)

Infiltration with mononuclear cells
Tissue destruction
Attempts at tissue repair
-vascular proliferation
-fibrosis

Cells involved in CI (5)

Macrophages
Lymphocytes
Plasma cells
Eosinophils
Mast cells

Cells involved in CI: Macrophage

Key cellular element in chronic inflammation
-monocytes recruited from blood
-transformed to macrophages in tissues
-activated by: microbial products, cytokines, other chemical mediators

Cells involved in CI: Macrophage Activation (2-3, 2)

Double-edged sword
Products
-eliminate injurious agents and initiate repair but also can cause tissue damage to microbes and host cells
-result in recruitment of other cells
-cause fibroblast proliferation, collagen deposition, and angiogenesis
Macrophage + Microbes and IFN-g = Inflammation and Tissue Injury
-via: cytokines, proteases, arachidonic acid metabolites, ROS, etc
Macrophage + IL-4 and other cytokines = Repair
-via: growth factors, fibrogenic cytokines, angiogenic factors

Cells involved in CI: Lymphocytes (4-2)

2:1 ratio CD4:CD8 tissues
Involved in both humoral and cell-mediated immune reactions
Recruited by chemokines and cytokines from activated macrophages
Communicate with macrophages:
-macrophages display Ags to T cells and elaborate membrane molecules and cytokines (IL-12) that stimulate T cells
-activated T cells elaborate cytokines (TNF, IL-17) that recruit monocytes

Cells involved in CI: Plasma Cells

Derived from B cells
-produce Abs, directed against
>foreigns Ags
>self-Ags
>altered tissue components

Cells involved in CI: Eosinophils (3-1)

Seen in reactions to parasites and immune responses mediated by IgE
Mobilized by eotaxin (chemokine)
Major basic protein = cationic protein within eosinophilic granules
-toxic to parasites

Cells involved in CI: Mast Cells (2-3)

Wide distribution in CT
Surface receptors bind Fc portion of IgE
-when IgE Abs bind their respective Ags, mast cells degranulate
>results in release of histamine
>seen in allergic and anaphylactic reactions

CI: Granulomatous Inflammation (3-2)

Immune reactions generally involved in generation of granulomas
Granulomas = focal accumulations of macrophages that have transformed into epithelioid macrophages (by IFN-g), surrounded by collar of lymphocytes and plasma cells
-foreign body granulomas: reaction to inert foreign bodies
-immune granulomas: response to immune T cell-mediated reactions to persisten Ags
Granuloma formation attempts to contain a difficult to eradicate agent

CI: Granulomatous Inflammation - Epithelioid Cells (2-2)

Have pale pink cytoplasm and indistinct cell borders
Fusion of epithelioid cells = Giant cells
-Langhans - peripherally arranged nuclei; horseshoe-shaped nuclei formation
-Foreign body - haphazardly arranged nuclei; choc chip cookie

CI: Granulomatous Inflammation - Examples (6)

Tuberculosis (Mycobacterium tuberculosis): Caseating granuloma, central necrosis, acid fact bacilli
Leprosy (Mycobacterium leprae): Noncaseating granulomas, acid fact bacilli
Syphilis (Treponema pallidum): Gumma, plasma cell infiltrate
Cat-scratch disease (Gram neg bacillus): Rounded or stellate granuloma, central granular debris
Sarcoidosis (Unknown): Noncaseating granulomas
Crohn disease (Immune reaction against intestinal bacteria, self-Ags): Noncaseating granulomas in intestinal wall

Systemic Effects of Inflammation (2)

Systemic changes associated with acute inflammation = acute phase response
Changes are secondary to cytokines, whose production is stimulated by bacterial products or inflammatory effects

Systemic Effects of Inflammation: Acute Phase Response (10)

Fever
Increase of acute phase proteins
Leukocytosis
Tachycardia
Increased BP
Rigors
Chills
Anorexia
Somnolence
Malaise

Systemic Effects of Inflammation: Fever (2)

Elevation of body temperature usually by 1-4 C
Pyrogen = any substance that causes a fever
-stimulate synthesis of prostaglandins in vascular and perivascular cells of hypothalamus
>Exogenous pyrogens: LPS on Gram (-)
>Endogenous pyrogens: IL-1 and TNF, increase cyclooxygenases which convert AA into prostaglandins

Systemic Effects of Inflammation: Fever - Prostaglandins (2)

Converted from AA via cyclooxygenases
(Esp. PGE2) stimulate production of NTs (such as cAMP) in hypothalamus which resets temperature set point

Systemic Effects of Inflammation: Acute Phase Proteins (5)

Mostly made in liver
Production increased by inflammation
Ex: C-reactive protein (CRP), Serum Amyloid A protein (SAA), and fibrinogen
Synthesis accelerated by cytokines (IL-6)
May act as opsonins and fix complement as well as assist in clearance of necrotic cell nuclei

Systemic Effects of Inflammation: Acute Phase Proteins - Anemia of Chronic Disease (2)

Impaired RBC production in association with chronic disease = common source of anemia in hospitalized patients in US
Inflammatory mediators (esp. IL-6) stimulate increase in hepcidin = involved in regulation of iron absorption, impedes transfer of iron to RBC precursors

Systemic Effects of Inflammation: Acute Phase Proteins - Erythrocyte Sedimentation Rate (3)

Normally, RBCs have a negative charge on their outer surface providing a repulsive force among them
Fibrinogen (acute phase protein) concentration increases with inflammation
Fibrinogen coats RBCs, blunting their charge and causing them to aggregate (makes them heavier)

Systemic Effects of Inflammation: Leukocytosis

Early phase: release of cells from post-mitotic reserve pool bone marrow
Later stages: colony-stimulating factors to increase proliferation of bone marrow precursors
"Left shift" = more immature forms of neutrophils are in blood
Normal count = 5,000-10,000 cells/uL, Counts generally rise to 15,000-20,000 cells/uL
Leukemoid reaction: very high WBC counts = 40,000-100,000 cells/uL
Bacterial infections cause neutrphilia
Viral infections cause lymphocytosis
Parasitic infections and allergic reactions cause eosinophilia
Some infections (like typhoid fever) may cause leukopenia (decrease in WBC count)

Systemic Effects of Inflammation: Sepsis (2)

Results when body responds to severe infection with production of very large amount of cytokines including TNF and IL1
Can result in DIC, metabolic changes, and CV failure aka septic shock

Defective Inflammation (2)

Increased susceptibility to infection
Delayed tissue repair: inflammation is normally crucial in removing debris and damaged tissues

Excessive Inflammation (4As)

Allergies
Autoimmune disease
Atherosclerosis
Alzheimers disease

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