Inflammation & Tissue repair Flashcards by Stacey Hansen

process of removing harmful agents and beginning repair process

Inflammation

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Acute inflammation is part of _____ immunity

Innate

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PAMPs are recognized by these receptors on endothelium, dendritic cells, macrophages, and WBCs

Toll-like receptors

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Necrotic tissue is recognized by these

Damage-associated molecular patterns (DAMPs)
Examples: uric acid, free DNA, low K+

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DAMPs are recognized by these receptors present on all cells

NOD-like receptors

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DAMPs are recognized by NOD-like receptor to produce ________

Inflammasome

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Inflammasome activates this enzyme

Caspase 1
(which activates IL-1 –> fever and leukocyte recruitment)

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Caspase 1 activates this

IL-1 –> fever and leukocyte recruitment

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Caspase 1 is involved in this process

DAMPs are recognized by NOD-like receptor to produce inflammasome, which then activates caspase 1 to activate IL-1 –> fever and leukocyte recruitment

= Recognition of threat; begins process of acute inflammatory response

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Dilation of small arterioles during acute inflammation is mediated by these

Histamines

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Dilation of small arterioles increases or decreases capillary blood flow?

Increases
Increased blood flow leads to redness (rubor) and warmth (color)

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____ blood flow allows leukocytes to leave circulation

Slow

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Leukocyte margination occurs during acute inflammation due to this

Stasis (slow blood flow)

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Leukocyte rolling is mediated by these

Selectins

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Leukocyte adhesion to endothelium is mediated by this interaction

Integrin : adhesion molecule interaction

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Leukocyte migration across vessel wall occurs in venules toward ______ gradient

Chemokine

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Increased vascular permeability occurs via these 2 mechanisms

Endothelial contraction (mediated by histamines, leukotrienes, bradykinins)
Endothelial damage (detachment from basement membrane)

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Endothelial contraction causes increased vascular permeability is mediated by these 3 things, and is rapid and short-lived

Histamines, Leukotrienes, Bradykinins

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Mechanism of increased vascular permeability that is rapid and short-lived (minutes)

Endothelial contraction

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Mechanism of increased vascular permeability that may be long-lived (hours to days); caused by thermal burns, some microbial toxins

Endothelial damage

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Increased vascular permeability allows _____ rich exudate to flow into tissues, causing swelling

Protein and cell-rich

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Key cell types recruited to site of acute inflammation are:

Phagocytes (neutrophil and macrophage)

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Earliest cell to arrive in acute inflammation

Neutrophils

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Main cell that arrives at site of acute inflammation

Macrophage

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Neutrophils arrive at site of acute inflammation after _____ hours

6-24 hours Earliest cell

Macrophages arrive at site of acute inflammation after _____ hours

24-48 (later; after neutrophils)

Step of acute inflammation that involves innate anti-inflammatory processes

Regulation

Membrane bound threat destruction can involve either of these

Phagolysosome / inflammasome

_______ apoptosis immediately after phagolysosome destruction is involved in the regulation step of acute inflammation

Neutrophil

2 Anti-inflammatory mediators involved in the regulation step of acute inflammation

IL-1:IL-1 receptor antagonist Bradykinin (kinases)

2 protease inhibitors involved in the regulation step of acute inflammation

Serum alpha-1 antitrypsin Neutrophil elastase

Excess tissue liquefaction is a possible outcome of acute inflammation that leads to this

Abscess

Liquefaction necrosis is a possible outcome of acute inflammation that involves _____ surrounded by fibrosis

PMNs (polymorphonuclear leukocytes = neutrophils, basophils, eosinophils)

Term that describes excess tissue liquefaction (pus forming)

Suppuration

Early repaired tissue; early scar

Granulation tissue

Cells that lay down collagen in scar formation

Fibroblasts

Immunodeficiency due to defective Beta chain of neutrophil integrins Prevents WBC:endothelial adhesion and tissue migration Delayed umbilical cord separation, followed by omphalitis Elevated WBC count Frequent/recurrent indolent bacterial infection May have skin/other sites necrotizing infection/abscess without pus

Leukocyte adhesion deficiency-1

Elevated WBC count and chronic skin infections with no pus are indicative of this condition

Leukocyte adhesion deficiency-1

3 clinical signs of Leukocyte adhesion deficiency-1

Delayed umbilican cord separation, followed by omphalitis Elevated WBC count Frequent/recurrent skin (or other sites) infections without pus

Leukocyte adhesion deficiency-1 is due to defective this

Defective Beta chain of neutrophil integrins

Leukocyte adhesion deficiency-1 prevents this

WBC:endothelial adhesion and tissue migration (due to defective beta chain of neutrophil integrins)

During phagocytosis, these structures surround and engulf particles into phagosome

Pseudopods

Organelle that produces materials to kill/digest offending agent

Lysosome

These are produced after phagolysosome fusion and during respiratory burst of neutrophils

ROS

How many components does NADPH oxidase have?

7; some in membrane, some in cytoplasm

This process results in the NADPH oxidase components being brought together to form active enzyme

Phagocytosis

Reactive nitrogen and reactive oxygen species are produced during this step in phagocytosis

Phagolysosome fusion

Immune deficiency due to defective phagosome-lysosome fusion Autosomal recessive mutation of LYST gene Affects neutrophil granules, melanocyte granules (partial albinism), neuronal axonal vesicle transport (peripheral neuropathy), platelet granules (bleeding disorder) Neutropenia Neutrophils and lymphocytes with LARGE fused granules Delayed microbial killing Mostly skin/mucosal infections Bleeding diathesis

Chediak-Higashi Syndrome

Chediak-Higashi Syndrome is due to defective this

Phagosome-lysosome fusion

Chediak-Higashi Syndrome is caused by an autosomal recessive mutation of this

LYST gene (LYSosomal Traffic regulator)

Chediak-Higashi Syndrome affects these 4 cells

Neutrophil granules (innate immune deficiency) Melanocyte granules (partial albinism) Neuronal axonal vesicle transport (peripheral neuropathy) Platelet granules (bleeding disorder)

Condition characterized by neutrophils and lymphocytes with LARGE fused granules

Chediak-Higashi Syndrome

Condition that can involve albinism, bleeding diathesis, peripheral neuropathy, delayed microbial killing

Chediak-Higashi Syndrome

Mediator of acute inflammation: Vasoactive amine released by mast cells (preformed and stored in granules) Released by various stimuli Causes vasodilation and venule permeability

Histamine

Histamine is released by these cells

Mast cells

2 actions of histamine

Vasodilation and Venule permeability

Mediator of acute inflammation: Arachidonic acid metabolite Produced by lipooxygenase in mast cells, other WBCs (preformed and stored in granules) Causes neutrophil chemotaxis and activation, smooth muscle contraction

Leukotrienes

Leukotrienes are a metabolite of this

Arachidonic acid

Leukotrienes are produced by this enzyme in mast cells and other WBCs

Lipooxygenase

3 actions of leukotrienes

Neutrophil chemotaxis Neutrophil activation Smooth muscle contraction

Mediator of acute inflammation: Arachidonic acid metabolite Produced by cyclo-oxygenase in mast cells, endothelium, platelets, other WBCs (preformed and stored in granules) Causes neutrophil chemotaxis and vascular permeability

Prostaglandins

Prostaglandins are metabolites of this

Arachidonic acid

Prostaglandins are produced by this enzyme in mast cells, endothelium, platelets, other WBCs

Cyclo-oxygenase

2 actions of prostaglandins

Neutrophil chemotaxis Vascular permeability

Lipooxygenase in mast cells and other WBCs produce this mediator of acute inflammation

Leukotrienes

Cyclo-oxygenase in mast cells, endothelium, platelets and other WBCs produces this mediator of acute inflammation

Prostaglandins

Mediator of acute inflammation that causes vasodilation and venule permeability

Histamine

Mediator of acute inflammation that causes neutrophil chemotaxis and activation, and smooth muscle contraction (Bronchus = bronchoconstriction) (Arterioles = Vasoconstriction)

Leukotrienes

Mediator of acute inflammation that causes neutrophil chemotaxis and vascular permeability

Prostaglandins

Endogenous pyrogen that sets thermoregulation at higher set-point

IL-2

Complement factors that induce histamine release, leading to vasodilation and permeability

C3a and C5a

C5a activates this enzyme, which produces leukotrienes and thromboxanes

Lipooxygenase

5 cardinal signs of acute inflammation

Rubor: tissue erythema Calor: tissue warmth Tumor: tissue swelling Dolor: tenderness/pain Functio laesa (loss of function)

Cardinal sign of acute inflammation that describes tissue erythema

Rubor

Cardinal sign of acute inflammation that describes tissue warmth

Calor

Cardinal sign of acute inflammation that describes tissue swelling

Tumor

Cardinal sign of acute inflammation that describes tendernoss/pain

Dolor

prolonged inflammatory response with co-existing tissue injury and repair attempts

Chronic inflammation

2 main cells of chronic inflammation

Macrophage > lymphocytes (mononuclear cells)

Macrophage becomes M1 cell when T cells secrete this

gamma IFN

Macrophage becomes M2 cell when T cells secrete this

IL-4 and IL-13

When T cells secrete gamma IFN, macrophages become this

M1 cell

When T cells secrete IL-4 and IL-13, macrophages become this

M2 cell

M1 cell produces these

NO and ROS, lysosomal enzymes (innate immunity)

M2 cell produces these

PDGF, FGF (initiates repair process)

2 morphological forms of macrophages

Mononuclear cell (kidney bean shaped nucleus) Multinucleated forms called Giant Cells

Type of T cells that secrete gamma interferon, activating M1 cells

Th1

Type of T cells that secrete IL-4, IL-5, and IL-13, activating M2 cells (tissue repair) and recruiting eosinophils

Th2

Type of T cells that secrete IL-17, recruiting neutrophils

Th17

Th17 cells secrete IL-17, recruiting these

Neutrophils

Type of T cells involved in bacteria, viruses, and autoimmune diseases

Th1 and Th17

Type of T cells involved with helminths and allergy

Th2

Type of cells that morphologically have small round nuclei, usually scant cytoplasm Activated forms have more cytoplasm

Lymphocytes

Type of cell that morphologically looks like "glass slippers"

Plasma cells

Type of chronic inflammation against persistent stimuli

Granulomatous inflammation

Granulomatous inflammation is a type of chronic inflammation against this

Persistent stimuli

Cell type involved in granulomatous inflammation

Macrophages

Change in macrophage morphology to epitheliod histiocyte ("banana shape") occurs during this May form multinucleated giant cells

Granulomatous inflammation

Released by macrophages and has elevated serum levels granulomatous inflammation

ACE

Released by macrophages during granulomatous inflammation and increases Ca absorption (hypercalcemia)

Vitamin D

How does granulomatous inflammation act to eliminate threats?

Walls off threats

2 typical persistent infections eliminated by granulomatous inflammation

Tuberculosis and Fungi

Granulomatous inflammation often contains this which appears morphologically pink/glassy

Fibrous/hyalinized material

Granulomatous inflammation that is caseating is seen in this infection

Tuberculosis

Immunodeficiency due to NADPH oxidase deficiency Results in inability to generate superoxide from NADPH Cannot generate ROS to kill microorganisms Poor fungal and bacterial killing by neutrophils Monocytes/macrophages are recruited Attempt to wall off infection with granulomas Early childhood onset Recurrent infections with catalase positive organisms Pneumonia Osteomyelitis Skin infections Lymphadenitis (lymph node enlargement) Ineffective phagocyte killing → attempt to contain with granulomas Also with draining skin nodules

Chronic granulomatous disease

Chronic granulomatous disease is due to a deficiency in this

NADPH oxidase Cannot generate ROS to kill microorganisms

Condition characterized by ineffective phagocyte killing; attempt to contain with granulomas

Chronic granulomatous disease

In Chronic granulomatous disease, there is ineffective phagocyte killing, so the body compensates by doing this

Attempt to contain infection with granulomas

Condition characterized by early childhood onset, recurrent infections with catalase positive organisms, skin infections, lymphadenitis

Chronic granulomatous disease

3 key cells in tissue repair

Macrophages (M2), fibroblast (collagen), endothelial cell (angiogenesis)

2 processes by which tissue repair occurs

Regeneration Connective tissue deposition

Describes tissues that are normally continuously regenerating Surface epithelium, bone marrow

Labile tissues

Tissues that are not dividing but able to stimulate cells to divide Stem cells, mature cells can re-enter cell cycle

Stable tissues

Tissues that are unable to divide and have no ability to regenerate Nervous, cardiac muscle

Permanent tissues

2 types of permanent tissues

Nervous and cardiac muscle

2 examples of labile tissues

Surface epithelium and bone marrow

Example of stable tissue

Stem cells

This process of tissue repair depends on proliferative potential of tissue (labile, stable, permanent)

Regeneration

Connective tissue deposition occurs during tissue repair in these 2 settings

Damage is too severe to restore with cellular regeneration Damage to organ incapable of regeneration (e.g. cardiac)

Connective tissue deposition produces this type of tissue

Granulation tissue - scar/fibrosis

3 components of connective tissue deposition during tissue repair

Angiogenesis (vessels) Connective fiber deposition Connective tissue remodeling

During angiogenesis, vasodilation occurs due to these 2 molecules

NO and VEGF Produces increased vascular permeability

NO and VEGF lead to this

Vasodilation; angiogenesis

Cells that separate from vessel and breakdown the basement membrane during angiogenesis

Pericytes

Family of enzymes that digest the basement membrane

MMPs (matrix matelloproteinases)

Cells that separate from vessel and breakdown basement membrane during angiogenesis

Pericytes

M2 cells produce TGF beta, which recruits these cells during connective tissue deposition

Fibroblasts

M2 cells produce this which recruits fibroblasts during connective tissue deposition

TGF beta

Cells which produce TGF beta, recruiting fibroblasts during connective tissue deposition

M2 cells

Granulation tissue that is diffuse or parenchymal

Fibrosis

Granulation tissue that is localized/defined

Scar

M2 cells produce this during connective tissue deposition, which recruits fibroblasts, stimulates collagen and fibronectin production, inhibits MMPs, and inhibits lymphocyte and other WBC activity

TGF beta

M2 cells produce TGF beta during connective tissue deposition, which stimulates the production of these

Collagen and fibronectin

M2 cells produce TGF beta during connective tissue deposition, which inhibits these enzymes

MMPs

M2 cells produce TGF beta during connective tissue deposition, which inhibits these cells

Lymphocytes and other WBC activity

At what point during connective tissue deposition in tissue repair is there granulation tissue?

After connective tissue fiber deposition; where M2 cells have produced TGF beta

Enzymes that are important during connective tissue remodeling of connective tissue deposition in tissue repair and allow collagen turnover

MMPs (matrix metalloproteases)

Type of fibroblasts that produce actin filaments

Myofibroblasts

Cells that are able to contract and reapproximate wound edges togethers during collagen tissue deposition of tissue repair

Myofibroblasts

At what point of collagen tissue deposition of tissue repair is there a mature scar? (dense collagen, mature vessels that are not leaky and have thicker walls)

After connective tissue remodeling

During this part of tissue repair, vessel number decreases, collagen density increases, myofibroblasts produce actin filaments, and WBCs depart

Connective tissue remodeling

Repair process for small wound and minimal separation

First intention tissue repair

Formation of this during first intention tissue repair provides scaffold for repair

Clot formation Attracts WBCs, fibroblasts, and endothelium

What happens <24 hours during first intention tissue repair?

Neutrophils begin removing necrotic tissue Epithelium at base begin proliferating

What happens day 3 during first intention tissue repair?

Surface covered by epithelium Macrophages replace neutrophils

What happens day 5 during first intention tissue repair?

Fibroblasts proliferate and begin type I collagen production

What happens week 2 during first intention tissue repair?

Scar is maturing

What happens at 1 month during first intention tissue repair?

Mature scar without WBCs, tensile strength ~70% of original

At what time of first intention tissue repair does: Neutrophils begin removing necrotic tissue Epithelium at base begins proliferating

<24 hours

At what time of first intention tissue repair does: Surface covered by epithelium Macrophages replace neutrophils

Day 3

At what time of first intention tissue repair does: Fibroblasts proliferate and begin producing collagen

Day 5

At what time of first intention tissue repair does: Scar is maturing

Week 2

At what time of first intention tissue repair does: Mature scar without WBCs; tensile strength ~70% of original

1 month

Repair process for wound without approximation (i.e. gaping wound; edges are not brought together)

Second intention

Type of collagen that forms provisional matrix during second intention tissue repair

Collegen type III

Type of collagen that replaces the provisional matrix during first intention tissue repair

Type I collagen

Why does second intention tissue repair have higher potential for inflammation-mediated damage and infection?

Gap is filled with larger volume of clot and necrotic material

Healing by second intention often produces this type of scar

Hypertrophic scar Raised above surrounding tissue

Tissue repair abnormality of excessive fibrous tissue where certain people are predisposed to this

Keloid formation (greatly raised about surrounding tissue)

Keloid formation is more common in people of this origin

African origin

Tissue repair abnormality of excessive fibrous tissue that disturbs organ function

Parenchymal fibrosis

Two cytokines that can lead to production of PG-E2 during fever

IL-1 and TNF

Compound that leads to increased preoptic nucleus set point during systemic inflammatory response syndrome

PG-E2

Occurs when WBCs are released from storage pools and increased production

Leukocytosis

Immune cells elevated in bacterial infection

Neutrophils

Immune cells elevated in viral infection

Lymphocytes

Immune cells elevated in bacterial parasitic infection and allergy

Eosinophils

C-reactive protein, erythrocyte sedimentation rate (ESR), serum amyloid A, hepcidin, and fibrinogen are examples of acute phase reactants that are seen in these states

Inflammatory states