week 3 - inflammation

inflammation

limits the spread of pathogens or injury

• natural and nonspecific response

common laboratory measures of inflammation

• increase in WBCs

• abnormal differential count

• acute-phase reactants

• fibrinogen

• C-reactives

lines of defense

1. natural barriers - physical, mechanical, biochemical (innate)

2. inflammation - respond to cellular or tissue damage (innate)

   • occurs in tissues with blood supply

   • nonspecific

   • initiates within seconds

3. adaptive immunity (acquired)

   • memory cells

microbiome

• naturally occurring, acquired early in life

• different anatomical locations have their own set

• doesn’t cause disease under normal conditions

  • may cause disease in immunocompromised people

• connected to first line of defense

ways microbiome interact with the body to foster healthy defense systems

• protective immune response and supports immune tolerance

• produces enzymes that digest fatty acids and polysaccharides

• synthesizes metabolites

• produces antibacterial substances

• competes with pathogens for nutrients

• blocks pathogen attachment to epithelium

symbiosis

collaboration between the body and microbiome to induce or suppress the immune response

• alterations can have negative effects on the body

• factors that contribute to alteration:

  • stress

  • diet

  • toxic metabolites from food

• can be intentionally altered to improve immunity

  • e.g, probiotics, prebiotics

purposes of inflammation

• prevents and limits infection for further damage

• limits and controls inflammation response

• interacts with components of the acquired immune system

• prepares the area of injury for healing

endothelial cells

• maintain blood flow and pressure by relaxing the blood vessels

  • through production of nitric oxide (NO) and prostacyclin (PGI2)

• inhibit platelet activation/prevent clotting

  • damage to endothelium promotes clotting

• retracts during inflammation to allow leukocytes to leave circulation to the site on injury

  • caused by histamine

mast cells

• cellular bags of granules found in loose connective tissue (e.g, skin, digestive tract, respiratory tract) close to blood vessels

• have to be in vasculature to act

• granules contain chemotactic factors that attract cells

  • neutrophil chemotactic factors attract neutrophils

  • eosinophil chemotactic factor of anaphylaxis (ECF-A) attracts eosinophils

• activated by physical injury, chemical agents, immunologic processes, TLRs

• mediators are released in two ways

  • degranulation

  • synthesis

degranulation

one way in which mast cells release mediators

• the release of histamine, chemotactic factors, and cytokines

histamine

constricts large blood vessels, dilates post-capillary venules

• causes endothelial cells to retract, making tissue more permeable = swelling

• receptors:

  • H1 receptor (pro-inflammation)

  • H2 receptor (anti-inflammatory)

H1 receptors

pro-inflammatory

• present in smooth muscle of bronchi, causing bronchoconstriction

• pain, itching, edema, vasodilation

H2 receptors

anti-inflammatory

• suppresses leukocyte function

• primarily present in stomach; stimulation results in increased production of HCI

synthesis

key points:

• arachidonic acid, cyclooxygenase, and prostaglandin are pain

  • key in pain

• enhance inflammation in general

platelets

stop bleeding, interact with components of the coagulation cascade

• degranulate mediators (serotonin)

• synthesize thromboxane A2 from prostaglandins

  • potent vasoconstrictor, causing platelet aggregation

what is the primary role of leukocytes and what are some types?

• primary role: phagocytosis

• types: GRANULOCYTES

  • neutrophils

  • eosinophils

  • basophils

neutrophils

• predominate in early inflammation response

• first to arrive at site of injury 6-12hrs after injury

• short lived and become part of the purulent exudate

• remove debris from sterile lesions (burns)

• phagocytose bacteria from non-sterile lesions

eosinophils

• the body’s primary defence against parasites

• controls inflammation by regulating vascular mediators released by mast cells

basophils

• similar to but are not mast cells

• important source for cytokine IL-4; regulator of adaptive immune response

• associated with allergies and asthma

what is the primary role of monocytes and macrophages?

phagocytosis

monocytes

• develop into macrophages

• produced in bone marrow then enter circulation, then arrive at site of injury (tissue) to develop into macrophages

macrophages

larger and more active phagocytes than monocytes

• important initiators of inflammation

• promotes wound healing

natural killer cells are classified as what type of cell?

lymphocytes

natural killer (NK) cells

• part of innate immunity

• recognize and eliminate pathogen-infected cells

dendritic cells

• link between innate and adaptive immune responses

• primary phagocytic cells located in peripheral organs and skin

• interacts with T-lymphocytes to initiate acquired immune response

• guides development of T-helper cells

what are the types of cellular receptors?

INNATE IMMUNITY

• pattern recognition receptors (PRRs) - recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs)

• toll-like receptors (TLRs) - direct and early recognition to let things in and out

  • stimulate mast cells

• complement receptors - recognize complement fragments

• scavenger receptors - promote phagocytosis

pre-phagocytic events

leukocytes called/attracted by chemotactic factors

• adhesion molecules produced

• marginalization - leukocytes stay close to endothelium

• diapedesis - leukocytes move along endothelium and leave circulation to site of injury

phagocytic events

leukocytes find pathogens through chemotaxis

• opsonization - recognition and tagging of pathogens

• engulfment

• formation of a phagosome

antiproteinase a1-antitrypsin

helps minimize destructive effects of the enzymes released by a dying phagocyte

cellular mediators of inflammation

• cytokines

• interleukins (IFs)

• interferons (IFs)

• chemokines

cytokines

family of intercellular signalling molecules; regulate innate or adaptive immunity

• can be pro-inflammatory or anti-inflammatory

• can be synergistic or antagonistic

• pleiotropic; actions depend on location

• includes interleukins, interferons, and tumor necrosis factor (TNF), and chemokines

interleukins (ILs)

• primarily produced by macrophages and lymphocytes

• helps regulate inflammation

• IL-1: fever (pro-inflammatory)

• IL-6: healing (pro-inflammatory)

• IL-10 anti-inflammatory

• transforming growth factor (TGF-B) - anti-inflammatory

interferons (IFs)

• produced by virally infected host cells in response to viral double stranded RNA

• modulates inflammation

• doesn’t kill infected cells directly, but prevents them from infecting additional healthy cells

• IFN-a and IFN-B: induce the production of antiviral proteins

• IFN-y: increases microbiocidal activities of macrophages

chemokines

• attract leukocytes to the site of inflammation

• produced by macrophages, fibroblasts, and endothelial cells

plasma protein systems

biochemical barriers against invading pathogens

• all contain inactive enzymes (proenzymes)

• sequentially activated (cascade)

• interactions among the 3 both control and inhibit each other

1. complement pathway/cascade

2. clotting/coagulation system

3. kinin system

complement pathway/cascade

can kill pathogens directly; works with other components of the inflammation response

3 pathways/stimulants:

1. classical - antibodies and antigens; causes a cascade effect

2. lectin - mannose-containing bacterial carbohydrates

3. alternative - gram-negative bacterial and fungal cell wall polysaccharides

functions:

• opsonization (C3b)

• anaphylatoxic activity from mast cell degranulation (C3a, C5a)

• leukocyte chemotaxis (C5a)

• cell lysis (C5b-C9; membrane attack complex)

clotting/coagulation system

• fibrinous mesh (fibrinogen to fibrin = clot)

• stops bleeding and the spread of pathogens

• provides framework for healing

• prepares pathogen for removal

pathways/stimulants:

• extrinsic - activated by tissue outside vascular space

• intrinsic - activated within the vascular space when the vessel wall is damaged

kinin system

assists and activates inflammatory cells

• primary product is bradykinin

  • causes vasodilation, pain, smooth muscle contractions (bronchoconstriction), vascular permeability

• kininase degrades kinins to limit the extent of inflammation

enzymes that inhibit the protein plasma systems

• carboxypeptidase - inhibits C3a and C5a (anaphylatoxic activities)

• kininases - inhibits kinin

• histaminase - inhibits histamine

• C1-esterase inhibitor (C1-inh) - inhibits all 3 pathways

stages of acute inflammation

• vascular stage - structural changes; vasodilation and vascular permeability

• cellular stage - influx of inflammatory cells (leukocytes, mainly neutrophils) at the site of injury

exudative fluids

exudate - fluid and cells

• serous exudate - watery; sign of early inflammation

• fibrinous exudate - thick, clotted; sign of later stages of inflammation

  • more cells from phagocytosis

• purulent (suppurative) exudate - pus; sign of bacterial infection

• hemorrhagic exudate - exudate containing blood; sign of bleeding

local manifestations of inflammation

• redness - vasodilation and increased blood flow

• heat - vasodilation and increased blood flow

• pain - exudate accumulation; prostaglandins, bradykinins

• swelling - exudate accumulations and vascular permeability

• loss of function may also occur

systemic manifestations of inflammation

• fever

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

  • acts directly on the hypothalamus

• leukocytosis

  • increased number of leukocytes

  • more immature cells

• increased plasma protein synthesis

  • acute-phase reactants

  • fibrinogen

  • C-reactives

chronic inflammation

• more than 2 weeks

• mainly due to an unsuccessful acute inflammatory response

• other causes:

  • high lipid or wax content in the microorganism

  • ability to survive in the macrophage

  • toxins

  • chemicals, particulate matter, physical irritants

characteristics of the chronic inflammatory response

• dense infiltration of lymphocytes and macrophages

• granuloma formation (cluster of WBCs)

• epithelioid formation

• giant cell formation

*no need to memorize, but these are all basically clusters of cells

innate immunity in neonates

• depressed respiratory and immune function

• neutrophils not effective in chemotaxis

• deficient complement system, especially alternative pathway

• susceptible to bacterial infections; vulnerable

innate immunity in the older adult

• impaired or delayed inflammation may be caused by chronic illness

• medications may affect wound healing

• infections are more common in older adults

allostatic load

a way to measure the cumulative wear and tear on the body

• repetitive use of multiple physiologic systems over time in response to environmental demands as a way to maintain internal homeostatic equilibrium

allostasis

what the body does to maintain the mind in homeostasis

allostatic overload

exposure to frequent stressors causes:

• repeated physiologic arousal

• lack of adaptation to stressor

• inability to shut off stress response

• insufficient response

accelerate wear and tear, impacts mediators, triggers inflammation