Chemical Mediators of Acute Inflammation

Lecture 12

What are some pathogen associated molecular pattern (PAMP) examples?

• lipopolysaccharide

• lipoteichoic acids

• mannose, peptidoglycan, bacterial DNA, N-formylmethionine

• double stranded RNA

• glucans

Molecular patterns are recognized by receptors on what?

• macrophages

• leukocytes

• mucosal epithelia

Molecular patterns (PAMPs) recognized by receptors trigger release of what?

chemokines and cytokines and cellular activation

Are pathogen associated molecular patterns (PAMPs) exogenous or endogenous?

exogenous (from bacteria/virus)

Are danger associated molecular patterns (PAMPs) exogenous or endogenous?

endogenous (produced within cell)

Exogenous and endogenous pathways trigger what?

immune response by activating pattern recognition receptors (PRRs)

What are the responses of acute inflammation?

• vasodilation

• increased vascular permeability

• smooth muscle contraction

• chemotaxis, leukocyte activation

• fever

• nausea

• pain

• tissue damage

Pain is intiated by activation of what?

nociceptors

Nociceptors innervate what?

• skin

• cornea

• genitourinary tract

• GI tract

• bones

• muscles

• and more

Nociceptors are activated by receptors that respond to what?

• chemicals

• heat/cold

• mechanical injury

• ATP

• cytokines (inflammatory mediators)

• microbial products

Nociceptors can release what to support inflammation in regard to vasodilation and activation of leukocytes?

neuropeptides

Why is the naked mole rat one of the species that has a reduced pain sensitivity?

overexpression of a sodium leak channel

Once activated and released or secreted, most inflammatory mediators have what type of half life, are detroyed how, and are scavenged by what?

• short half lives and decay rapidly

• are destroyed enzymatically

• are scavenged by protective mechanisms such as antioxidants

Chemical mediators are preformed, synthesized, or derived from what?

plasma

What are the chemical mediators of acute inflammation?

• vasoactive amine

• plasma proteases

• lipid mediators

• cytokines and chemokines

• fragments of degraded molecules

• reactive oxygen species

Vasoactive amines affect what?

blood vessel diameter

Plasma proteases are enzymes that function in what?

inflammation and tissue remodeling

Lipid mediators are molecules from what?

fatty acids in cell membrane

Cytokines and chemokines are proteins that act as what?

messengers of the immune system helping with regulation

What mediators of acute inflammation are vasodilators?

• nitric oxide

• bradykinin

• prostaglandins

• leukotrienes (B4)

What mediators of acute inflammation initiate fever?

• cytokines (IL-1, TNF, IL-6)

• prostaglandins

What mediators of acute inflammation cause nausea?

• cytokines (IL-1, TNF, high mobility group factors)

What mediators of acute inflammation affect cell permeability?

• vasoactive amines (histamine, substance P, bradykinin)

• complement factors (C5a, C3a)

• fibrinopeptides and fibrin breakdown products

• prostaglandins

• leukotrienes (B4, C4, D4, E4)

• PAF, substance P

• cytokines (IL-1, TNF)

What mediators of acute inflammation affect smooth muscle contraction?

• histamine

• serotonin

• C3a

• bradykinin

• PAF

• leukotriene D4

What mediators of acute inflammation cause pain?

• bradykinin

• prostaglandins

What mediators of acute inflammation are responsible for chemotaxis and leukocyte activation?

• complement factor C5a

• leukotriene B4

• Chemokine IL-8

• alpha and beta defensins

• LPS, peptidoglycan, teichoic acid

• surfactant proteins A and D, mannan-binding lectin

• Cytokines IL-1 and TNF

What cells are the main source of histamine?

• basophils

• mast cells

What are the major effects of histamine (hint: there’s 6)?

• vasodilation

• increased microvascular responses

• neural reflexes, vagal reflexes, bronchial constriction

• pain and itching

• tachycardia

• eosinophil chemotaxis

Which histamine receptors are located on leukocytes?

H1 and H4

Which histamine receptors are located on gastric mucosa and nerve terminals?

H2 and H3

Which histamine receptor is involved in the pathogenesis of allergies?

H1

H1 receptor activation in response to allergic bronchiolitis in cats and horses results in what?

increased vascular permeability, leading to serous inflammation in the bronchi and bronchioles

H1 receptor antagonists (antihistamines) reduce symptoms associated with what?

allergic rhinitis

What cells produce histaminases that degrade histamine and help mitigate its effects?

eosinophils

Which chemical mediator is a vasoactive amine that affects blood vessel diameter and a neurotransmitter?

serotonin

Serotonin is located within what cells?

platelets

Serotonin is released from platelets in which scenarios?

• contact with collagen in an exposed basement membrane from areas of endothelial necrosis and detached cells

• thrombin from activation of the coagulation cascade

• adenosine diphosphate released from injured endothelial cells

• immune complex activation of the complement cascade

What are the proteins that regulate blood pressure, inflammation, and pain?

kinins

Kinins are generated from what?

• plasma kinin

• tissue kinin pathway

Kinins modulate what to impact inflammation?

clotting and complement cascades

Bradykinin is what type of molecule?

pro inflammatory

What are the effects of bradykinin?

• increased vascular permeability

• vasodilation

• increased senstiivty to pain

• smooth muscle contraction

• increased arachidonic acid metabolism

• hypotension

• bronchoconstriction

What is another name for substance P?

tachykinin

Substance P (tachykinin) is made where?

in nerve fibers of the lungs and GI tract

What is the function of substance P (tachykinin)?

• vasoconstriction, vasodilation, increased permeability changes leading to edema, leukocyte activation, chemotaxis

• activation and degranulation of mast cells, basopihls, and eosinophils and their release of histamine

Histamine binds what receptors of nerve fibers?

H3

Substance P is released from sensory nerve fibers in skin and mucous membranes induced by what?

capsaincinoids (capsaicin)

With repeated exposure, capsaicin depletes substance P from nerve endings and ultimately does what?

reduces pain sensitivity in the affected area

Complement proteins C1 to C9 are synthesized where before circulating in blood?

the liver

The complement cascade is activated by what?

• microbial molecules (endotoxins)

• aggregated immunoglobulins

• complex polysaccharides

What are the effects of the complement cascade?

• proinflammatory

• chemotactic

• opsonizing

• antigen solubilizing

• antibody inducing

• permeability enhancing

• microbicidal (cell lysis)

Why is the complement cascade benficial?

complements circulating cells and antibodies to remove microbes and damaged cells

Nearly what percentage of serum proteins are complement factors?

10%

Activation of complement proteins evantually results in formation of what?

membrane attack complex (MAC)

What is the purpose of the membrane attack complex. (MAC)?

perforates the cell membranes of foreign invaders and naive host cells

What are the three complement pathways?

• classical

• alternative

• lectin

The classical complement pathway is activated by what?

antibody complexes

The alternative complement pathway is activated by what?

microbial products (lipopolysaccharide / endotoxin)

The lectin complement pathway is activated by what?

lectin binding sugars on bacteria/fungus

Describe the complement cascade (short and sweet, not specific).

• activation/fixation of complement proteins

• form membrane attack complex

• MAC perforates cell membranes of pathogens and naive cells

• inflammatory and immature effects

As a result of cell injury, cell membranes are rearranged to create a lipid mediators derived from what?

arachidonic acid

What are arachidonic acid metabolites?

inflammatory mediators derived from cell membranes

Arachidonic acid metabolites work intracellular and extracellular signals to influence what?

• coagulation cascade

• acute inflammatory response

What are the two pathways to create arachidonic acid metabolites?

• cyclooxygenase pathway

• lipooxygenase pathway

Which arachidonic acid metabolites result from the cyclooxygenase pathway?

• prostacyclin

• prostaglandin

• thromboxane

Which arachidonic acid metabolite results from the lipooxygenase pathway?

leukotrienes

What is the purpose of prostaglandin?

cause pain and inflammation

What is the purpose of thromboxane?

cause platelet aggregation

What is the purpose of leukotrienes?

cause bronchoconstriction, asthma attacks, smooth muscle contraction

What enzyme causes the release of arachidonic acid from the phospholipid membrane?

phospholipase A2

NSAIDs like Rimadyl and Banamine inhibit what enzymes? Which pathway of arachidonic acid metabolites is affected?

inhibit COX enzymes, inhibits cyclooxygenase pathway

What is a subtype of cytokine that promotes leukocyte chemotaxis and migration across capillaries?

chemokines

IL-5 is what type of cytokine that does what?

• pro-inflammatory

• stimualtes eosinophils

IL-4 is what type of cytokine that does what?

• anti-inflammatory

• inhibits production of proinflammatory cytokines

What is the purpose of cytokines?

they suppress or enhance expression of other cell types during the inflammatory response

What is part of the cytokine family and is produced in response to viruses, viral infected cells, parasite and neoplasia?

interferons

What is the purpose of interferons?

• inhibit viral replication

• activate natural killer cells and macrophages

• increase antigen presentation to T cells

• can be used for therapeutics (cancer, viral infections)

What chemical mediators of inflammation are cell derived and preformed?

• histamine

• serotonin

What chemical mediators of inflammation are cell derived and synthesized de novo?

• arachidonic acid metabolites

• platelet activating factor

• nitric oxide

• reactive oxygen species

• cytokines

• chemokines

What chemical mediators of inflammation are plasma derived?

• complement (C3a, C3b, C5a)

• Factor XIII activation (coagulation system, kinin system)

What chemical mediator is released from neutrophils and macrophages after exposure to chemolines and immune complexes?

oxygen derived free radicals

What neutralizes free radicals?

antioxidants

Nitric oxide is synthesized by what?

• endothelial cells

• macrophages

• brain neurons

What are the functions of nitric oxide?

• causes vasodilation by relaxing vascular smooth muscle cells

• inhibits platelet aggregation

• inhibits mast cell induced inflammation