Chapter 7 - innate immunity: inflammation and wound healing

Types of immunity

• innate resistance

• Adaptive (acquired) immunity

innate resistance

• natural barriers and the inflammatory response

adaptive (acquired) immunity

• immunity developed after exposure to antigens, involving specific lymphocyte responses and memory.

Lines of defense - immunity

• first line

• Second line

• Third line

First line - immunity defense

• natural barriers - physical, mechanical and biochemical

Second line - immunity defense

• Inflammation

Third line - immunity defense

• adaptive (acquired) immunity

Physical and mechanical barriers - 1st line of defense

• skin and low temp/pH of skin

• Linings of the gastrointestinal, genitourinary and respiratory tracts

• Highly interconnected junctions

• Sloughing off of cells

• Coughing and sneezing

• Vomiting

• Urinating

• Mucus and cilia

Biochemical barriers - 1st line of defense

• synthesize and secrete substances to trap or destroy microorganisms

  • Antibacterial peptides in mucus, perspiration, saliva, tears and earwax

• Antimicrobial peptides

• Normal microbiome

  • Inhibits colonizations by pathogens; releases chemicals that prevent infections

antimicrobial pepetides

• Catholicizing

• Defending

• Collectins

Normal microbiome - vaginal

• lactobacillus

Normal microbiome - intestinal

• ammonia

• Phenols

• Indoles

2scd line of defense - inflammatory response causes

• infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes and radiation

2scd line of defense - inflammatory response

• cellular and chemical components

• Nonspecific - take place in the same pway

• Rapidly initiated

• Non memory cells

2scd line defense - inflammatory cardinal signs

• redness

• Heat

• Swelling

• Pain

• Loss of function

2scd line defense - inflammatory vascular response

• blood vessel dilation

• Increased vascular permeability and leakage

• WBC adherence to the inner walls of the vessels

• Migration through the vessels (diapedesis)

2scd line defense - inflammatory response in the cells

• once in the tissues the cells and chemicals associated with he inflammatory response

  • Prevent and limit infection and further damage

  • Limit and control the inflammatory process

  • Interact with components of the adaptive immune system

  • Prepare the area of injury for healing

Plasma protein systems

• protein systems that provide a biochemical barrier against invading pathogens

• Complement system

• Clotting system

• Kinin system

What do all plasma protein systems contain?

• inactive enzymes (pro enzymes)

• Sequentially activated-cascade

  • 1st pro enzyme if converted to an active enzyme

  • The activation of the first component of a system results in sequential activation of other components

Complement system

• can destroy pathogens directly

• Activates or collaborates with every other component of the inflammatory response

complement system - pathways

• classical - antibodies and antigens

• Lectin - mannose containing bacterial carbohydrates

• Alternative - gram-negative bacterial and fungal cell wall polysaccharides

complement system - functions

• Anaphylatoxic activity resulting in mast cell degranulation

• Leukocyte chemotaxis

• Opsonication

• Cell lysis

Clotting (coagulation) system

• forms a fibrinous mesh at an injured or inflamed site

• Main substance in fibrinous mesh is insoluble protein called fibrin

  • Prevents the spread of infection

  • Keeps microorganism and foreign bodies at the site of inflammation for removal

  • Forms a clot that stops bleeding

  • Provides a framework for repair and healing

clotting (coagulation) system

• extrinsic - activated by the tissue factor outside the vascular space

• Intrinsic - is activate din the vascular space when the vessel wall is damaged

Kinin system

• causes dilation of blood vessels

  • Pain

  • Smooth muscle contraction

  • Vascular permeability

  • Leukocyte chemotaxis

• Functions to activities and assist inflammatory cells

• Primarily bradykinin

• Kinin Ashe degrade Kinins

Plasma protein systems - continued

• interactions among the 3 plasma protein systems are finely regulated to prevent injury to the hot tissue and to guarantee activation when needed

• Multiple mechanisms are available to either activate or inactivate (regulate) these plasma protein systems

Plasma protein systems - interactions

• interactions among the 3 plasma protein systems control inflammation and inhibit the 3 plasma protein systems

Carboxypeptidase

• inhibits C3a and C5a

Histaminase & arylsulfatase

• inhibits histamine

Kinase

• inhibits kinins

C1 - esterase inhibitor

• inhibits complement

Cellular mediators

• mast cells

• Granulocytes (neutrophils, eosinophils, basophils)

• Monocytes & macrophages

• Natural killer cells and lymphocytes

• Cellular fragments (plts)

Biochemical mediators

• originate from destroyed or damaged cells

• Modulate the localization and activates of other inflammatory cells

• Tissue regeneration or repair (resolution)

Cell surface or cellular receptors

• pattern recognition receptors (PRRs)

  • Toll-like receptors

  • Complement receptors

  • Scavenger receptors

• PAMPs

• Damage-associated molecular patterns (DAMPs)

toll-like receptors (TLRs)

• recognize pathogen-associated molecular patterns (PAMPs)

Complement receptors

• recognize complement fragments

Scavenger receptors

• promote phagocytosis

When is the inflammatory response initiated

• when tissue injury occurs or when PAMPs are recognized by PRRs on cells of the innate immune system

Chemokines or cytokines

• regulate innate or adaptive resistance by affecting other neighboring cells

• Either pro inflammatory or anti inflammatory

• Actions are pleiotropic

• Either synergistic or antagonistic

• Include cytokines - TNF, interleukins or interferons

Interleukins - cytokine

• are produced primarily by macrophages and lymphocytes in response to a microorganisms or stimulation by other products of inflammation

• Help regulate inflammation

• Many types exist

interleukins (ILs) - examples

• IL-1

• IL-6

• IL-10

• Transforming growth factor-beta (TGF-b)

IL-1

• proinflammatory cytokine

• Causes fever

IL-6

• proinflammatory cytokine

• Helps with healing

IL-10

• anti inflammatory cytokine

TGF-B

• anti inflammatory cytokine

Interferons (IFNs) - cytokine

• protect against viral infections

• Produces and released by virally infected host cells in response to viral double stranded ribonucleic acid (RNA)

• Do not kill viruses but prevent them from infecting additional healthy cells

Interferons (IFNs) - examples

• IFN-a and IFN-B

• IFN-y

IFN-a and IFN-b

• induce the production of antiviral proteins

IFN-y

• increases microbiocidal activity of macrophages

Chemokines

• induce WBC chemotaxis

• Produced by macrophages, fibroblasts and endothelial cells

CC-chemokines

• affect mainly monocytes, lymphocytes and eosinophils

CXC- chemokines

• generally affect neutrophils

Mast cells

• cellular bags of granules located in loose connective tissues close to blood vessels

  • Spine, digestive lining, and repertory tract where they are located

mast cells - activation

• physical injury

• Chemical agents

• Immunologic process

• TLRs

• Chemicals released by degranulation or synthesis of lipid -derived chemical mediators

mast cells degranulation - releases histamine

1) releases histamine

2) causes temporary and rapid constriction of the large blood vessels and dilation of the post capillary venues

3) endothelial cells that line the capillaries are retracted

4) receptors - H1 receptors induces bronchoconstriction, H2 receptors induces the secretion of gastric acid

H1 receptor

• prroinflammaroty

• Is present in smooth muscle cells of the bronchi

• Includes bronchoconstriction

H2 receptor

• anti inflammatory

• Is present on parietal cells of the stomach mucosa

• Induces the secretion of gastric acid

Mast cell degranulation - chemotactic factors

• neutrophils chemotactic factor

  • Attracts neutrophils

• Eosinophils chemotactic factor of anaphylaxis (ECF-A)

  • Attracts eosinophils

Mast cell synthesis of mediators

• leukotrienes

• Prostaglandins

• Platelet-activating factors

Leukotrienes

• are the product of arachnids in acid from mast cell membranes

• Have similar effects to histamine

• More important in the later stages of inflammation

Prostaglandins

• have a similar effects to leukotrienes

• Induce pain

Platelet-activating factor

• effects is similar to leukotrienes

• Activate platelets

Endothelium

• maintains normal blood flow

• Endothelial cells produce nitric oxide (NO) and prostacyclin (PGI2)

• Damage to endothelium promotes clotting

What does NO and PGI2 do?

• maintain blood flow and pressure and inhibit platelet activation

• NO maintains vascular tone

what does the endothelium do during inflammation?

• expresses receptors that help leukocytes leave the circulation

• Retracts to allow fluid to pass into the tissues

Platelets

• Aka thrombocytes

• Activation of platelets stops bleeding and degranulation

• Cellular fragments formed frommegarkaryocytes

Neutrophils - phagocytes

• aka polymorphonuclear neutrophils (PMNs)

• Predominate in early inflammation responses

• Ingest bacteria, dead cells and cellular debris

• Short lived and become components of the purple net exudate (pus)

• Primary role

  • Removal of debris in sterile lesions

  • Phagocytosis of bacteria in nonsterile lesions

eosinophils - phagocytes

• provide the defense against parasites and regulate vascular mediators

• Help control vascular effects of inflammation

Basophils - phagocytes

• are similar or but are not mast cells

• Are an important source for cytokine IL-4

• Are associated with allergies and asthma

• Role is uncertain

Dendritic cells - phagocytes

• provide link between innate and acquired immune responses

• Phagocytes cells

• Located in peripheral organs and spine

• Migrate to lymphoid tissue and interact with T lymphocytes to cause acquired immune responses Phagocytes

• Guide development of T-cells (helper cells)

Monocytes - phagocytes

• produces in the bone marrow, enter circulation, migrate to the inflammatory site and develop into macrophages

• Precursors to macrophages in tissues

  • Kupffer cells (liver)

  • Alveolar macrophages (lungs)

  • Microglia (Brain)

macrophages - phagocytes

• larger and more active as phagocytes than monocytes and are important cellular initiators of inflammation they help in wound healing

Phagocytosis

• process by which a cell ingests and dispose of foreign material

• Destruction of microorganisms and cellular debris

• Production of adhesion molecules occurs

• Marination (pavementing) occurs

  • Leukocytes adhere to endothelial cells

• Diapedesis occurs

  • Cells emigrate through the endothelial junctions

steps of phagocytosis

• opsonization

• Recognition

• Adherence

• Engulfment

• Phagosome formation

• Fusion with lysosomal granules

• Destruction of the target

Opsonization

• glue between the phagocyte and the target cell by C3b making the foreign cell more susceptible by phagocytosis

Engulfment

• small pseudopods surround adherent microorganisms

Fusion with lysosomal granules

• creates a phagolysosome

A1-antitrypsin

• helps minimize the destructive effects of the enzymes released by the dying phagocytes’

Natural killer (NK) cells

• recognize and eliminate cells that are infected with viruses and cancer cells in the blood

Lymphocytes

• main components of the adaptive immune response

Local manifestations of inflammation

• result from vascular changes and corresponding leakage of circulating components into the tissue

• Heat - vasodilation and increased blood flow

• Redness- vasodilation and increased blood flow

• Swelling - exudate accumulations and fluid fri=om capillary permeability

• Pain - pressure exerted by exudate accumulations, prostaglandins and bradykinins

• Loss of function

Functions of local manifestations of inflammation

• dilute toxins

• Carry plasma proteins and leukocytes to the injury site

• Carry bacterial toxins and debris away from the site

Exudative fluids

• fluids and cells such as protein and debris

Serous exudate

• watery exudate - indicates early inflammation

Fibrinous exudate

• thick, clotted exudate - indicates more advanced inflammation

Purulent (suppuration) exudate

• pus - indicates a bacterial infection

Hemorrhagic exudate

• exudate containing blood - indicates bleeding

Systemic manifestations of inflammation

• fever

  • Caused by exogenous and endogenous (IL-1) pyrogens

  • Acts directly on the hypothalamus

• Leukocytosis

  • Increased number of circulating leukocytes

  • Left shift, increase in immature cells (bands)

• Increased plasma proteins synthesis

  • Acute-phase reactants

    • C-reactive protein, fibrinogen, haptoglibing, amyloid A and ceruloplasmin

Chronic inflammation

• inflammation that lasts 2 weeks or longer

• Often relates to an unsuccessful acute inflammatory response

Characteristics - chronic inflammation

• dense infiltration of lymphocytes and macrophages

• Granuloma formation

• Epithelial cells such formation

• Giant cell formation

Wound healing

• regeneration

• Resolution

• Repair

Regeneration - wound healing

• most favorable outcome

Resolution - wound healing

• returning injured tissue to the original structure and function

Repair - wound healing

• replacement of destroyed tissue with scar tissue

• Scar tissue - primarily composed of collagen to restore the tensile strength of the tissue

Wound healing process

• filling in the wound

• Sealing the wound (epithelialization)

• Shrinking the wound (contraction)

Primary intention - wound healing

• wounds that heal under conditions of minimal tissue loss

• Original tissue structure and function that have been restored

Secondary intention - wound healing

• wounds that require significantly more tissue replacement - open wound

• Wounds that cause scar formation

Wound healing phases

1) inflammation

2) reconstruction

3) remodeling and maturation

Phase 1 - inflammation

1) coagulation and infiltration - platelets, neutrophils, macrophages

2) fibrin mesh of blood clot acts as scaffold

3) platelets release growth factors

4) neutrophils and macrophages clean the wound

5) debridement occurs

6) blood vessels and lymph drain away debris

7) vascular dilation and permeability reverse

phase II - reconstruction

1) wound begins to heal

2) healing begins 3-4 days after the injury and continues for 2 weeks

3) fibroblast proliferation occurs

4) collagen synthesis by fibroblasts

5) epithelialization - cells from healthy tissue grow into wound

6) wound contracts through the actions of myofibroblasts

7) cellular differentiation occurs