Th2 Pathway

Dendritic phagocytosis of allergen

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Allergen presented on MHC II

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CD4+ cells becomes activated

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Th0 cells release IL-4 and become Th2 cells

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Th2 cells release IL-4 and IL-13

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B-cell transformation into IgE-producing Plasma cells

Following the Th2 pathway, B-cells transform into IgE-producing Plasma cells

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IgE is released

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IgE binds to FcεRI on mast cells (and basophils)

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Allergen cross-links IgE and FcεRI

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Mast cell is activated

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Degranulation occurs

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Release of histamine as well as prostaglandins D4, PGF2α, TXA2, and leukotrienes

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Bronchoconstriction

• Stimulates Th2 development from undifferentiated T-cells
• Inhibitory effects on Th1 pathway
• Stimulates B cells to switch from producing IgG to producing IgE

• Produced by Th2 cells and mast cells
• Stimulates development of eosinophils from bone marrow precursor cells
• Prolongs the survival eosinophils

IL-13 binds to heterodimer receptor, composed of IL4Rα and IL13Rα1

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Activation and release of STAT6 from receptor

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Dimerization of STAT6

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Nuclear transcription

Binding of IL13 to its receptor also results in increased expression of Acid Mammalian Chitinase (AMC)

• PGF2α -- also enhances histamine action
• PGD2
• TXA2

• Can form LTD4
• Airway edema, bronchospasm, mucus secretion, microvascular permeability

• Can form LTE4
• Airway edema, bronchospasm, mucus secretion, microvascular permeability

Mast cell degranulation results in activation of phospholipase A2

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PA2 cleaves arachidonoyl group of phospholipids

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Arachidonic acid is converted to Leukotriene A4 by 5-lipoxygenase

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LTA4 can become LTB4 or LTC4

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Generation of LTC4 results in formation of LTD4 or LTE4

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Leukotrienes bind to CysLT1 receptor

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Airway edema, bronchospasms, mucus secretion, microvascular permeability

• Occurs hours after initial provocation
• Involves recruitment and activation of eosinophils, basophils, neutrophils, and macrophages
• Leads to airway hyperresponsiveness

Airway Remodeling

• Nonspecific hyperresponsiveness and worsening of asthma
• Epithelial cell damage and fibrosis
• Inflammatory mediators
• Muscle thickening
• Mucus hypersecretion -- goblet cell hyperplasia
• IL5 appears to have a role in airway remodeling through TGFβ

1.  Relax bronchial smooth muscle

• Mediated by increase in cAMP --> MLCK phosphorylated (by PKA) and inactivated --> MLCP activated --> MLC dephosphorylated --> smooth muscle relaxation
• Increases conductance of large Ca2+ sensitive K+ channels in airway smooth muscle (independent of adenylyl cyclase activity and cAMP production)

2.  Inhibits release of inflammatory mediators and cytokines

• Not sufficient enough to be used alone as anti-inflammatory therapy

Beta2 Receptor Agonist

• More selective for Beta2 receptors than isoproterenol
• Binding to beta receptors results in relaxation of bronchial smooth muscle, which relieves bronchospasm, reduces airway resistance, facilitates mucous drainage, and increases vital capacity
• Can inhibit degranulation and release of inflammatory autocoids from mast cells
• Actions on peripheral vascular smooth muscle causes vasodilation and a modest decrease in diastolic blood pressure
• Weaker Beta2 agonist than other drugs -- not used that much anymore
• Has Beta1 receptor agonism = increased chronotropy/inotropy

• Short-acting provides immediate relief
• LABA's have longer duration of action
• Long acting cannot be administered alone -- combo with corticosteroids -- due to asthma related deaths
• With LABA's, tolerance might develop to the bronchodilatory effect

• Inhalation is preferred route
• Topical provides more rapid response, greater protection against provocation, and fewer side effects

Short Acting Beta2 Agonist

• Combination of R and S isomer
• R is responsible for bronchodilation as well as producing side effects
• S is responsible for pro-inflammatory and induces bronchial hyperreactivity?
• S-albuterol is metabolized 12x slower than R-albuterol

Short Acting Beta2 Agonist

• R isomer of albuterol
• R is responsible for bronchodilation as well as producing side effects
• Has not shown any advantage over racemic albuterol

Partial Beta2 Agonist

• Compared to full agonists, partial has fewer side effects
• Cannot protect against bronchoconstrictors as well as full agonist

Long Acting Beta2 Agonist

• Compared to partial agonists, full agonists have greater side effects
• Greater protection against bronchoconstrictors than partial agonist

• Tremor
• Tachycardia
• Increased QTc interval -- ventricular arrhythmias and death
• Hyperglycemia
• Hypokalemia

Short Acting Beta2 Agonist

• Quick onset/short duration of action

Short Acting Beta2 Agonist

• Quick onset/short duration of action

Inhaled Short acting Beta2 agonist!

Albuterol, Pirbuterol, Terbutaline

TOLERANCE

• Downregulation of Beta2 receptors
• Decrease affinity for Beta2 agonist
• Cross-tolerance may occur as well

• Increase the number of Beta2 adrenergic receptors and receptor responsiveness
• Reduce mucus production and hypersecretion
• Reduce bronchial airway hyperreactivity
• Decrease pro-inflammatory cytokine release
• Prevent and reverse airway remodeling

IL-1β, TNFα bind to receptor

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Activates IKKβ

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IKKβ phosphorylates inhibitory protein IκBα that is normally complexed with NF-κB

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NF-κB is activated and dimerizes (p50 and p65)

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p50 and p65 dimer mobilizes to nucleus

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Activates Histone Acetyltransferase (HAT)

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HAT acetylates histone H4

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Increased transcription of inflammatory genes

Corticosteroids bind to GR

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GR monomer translocates to nucleus

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Inhibits Histone Acetyltransferase (HAT) activity

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Recruits Histone Deacetylase-2 (HDAC2)

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Histone H4 is deacetylated

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Repression of inflammatory gene transcription

Corticosteroids bind to GR

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GR dimerizes and translocates to nucleus

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GR dimer binds to Glucocorticoid Response Elements (GRE) in the promoter region of steroid-sensitive genes and to coactivators that have intrinsic HAT activity

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Acetylation of lysines on histone H4

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Transcription of genes encoding anti-inflammatory proteins and Beta2 receptors

• Retention of Na+ and fluid
• Weight gain
• High blood pressure
• Facial puffiness
• Adrenal suppression, hyperadrenocorticism
• Mood disturbances
• Psychotic behavior
• Increased frequency and/or severity of infections
• Osteoporosis (long-term)
• Impaired healing

Inhaled Corticosteroid

• Provides potent topical anti-inflammatory effects with fewer systemic side effects
• Reduces bronchial airway hyperreactivity

Inhaled Corticosteroid

• Provides potent topical anti-inflammatory effects with fewer systemic side effects
• Reduces bronchial airway hyperreactivity

Inhaled Corticosteroid

• Provides potent topical anti-inflammatory effects with fewer systemic side effects
• Reduces bronchial airway hyperreactivity

• Thrush
• Dry Mouth
• Growth Retardation in Kids

• Osteoporosis
• Cataracts
• Adrenal Insufficiency

1.  Inhibitor of PDE 3 and 4

• Allows for build up of cAMP and subsequent bronchodilation

2.  Adenosine antagonism

• Theophylline is structurally similar to adenosine
• Adenosine can provoke bronchoconstriction in asthmatic patients and antagonize theophylline-induced bronchodilation

3.  Restores HDAC2 Activity

• Restores senstivity to glucocorticoids
• Reduces inflammatory gene expression

At lower concentrations:

• nausea
• vomiting
• insomnia

At high concentrations:

• seizures
• cardiac arrhythmias
• death

1.  Sympathomimetics

• Caffeine -- theophylline is a dimethylxanthine
• Results in excessive sympathetic stimulation
• Tremors, insomnia, seizures, cardiac arrhythmias

2.  Beta2 Agonist

• May amplify hypokalemic effects

3.  Theophylline Metabolism Inhibitors

• Zileutin (CYP1A2 inhibitor)
• Erythromycin
• Clarithromycin
• Beta Blockers

4.  Theophylline Metabolism Inducers

• Barbiturates
• Carbamezepine
• Rifampin

• Blocks Cl- and Ca2+ Entry Channels?
• Inhibits release of inflammatory mediators from mast cells and other inflammatory cells
• Inhibits IgE production
• Inhibits neutrophil superoxide generation
• Inhibits mast cell degranulation
• Inhibits immediate allergic response to allergen challenge or exercise challenge

• Blocks Cl- and Ca2+ Entry Channels?
• Inhibits release of inflammatory mediators from mast cells and other inflammatory cells
• Inhibits IgE production
• Inhibits neutrophil superoxide generation
• Inhibits mast cell degranulation
• Inhibits immediate allergic response to allergen challenge or exercise challenge

5-Lipoxygenase Inhibitor

• Prevents the formation of leukotrienes
• Anti-inflammatory properties
• Does not replace the use of inhaled short-acting Beta2 agonists

• Liver toxicity
• Headache
• Irritations of gastric mucosa

Cysteinyl Leukotriene 1 Receptor Antagonist

• Inhibits pro-inflammatory actions of leukotrienes
• Decreases edema, mucus secretion, and eosinophil chemotaxis
• Decreases bronchial hyperresponsiveness
• Can produce bronchial relaxation -- still need a short acting Beta2 agonist

Cysteinyl Leukotriene 1 Receptor Antagonist

• Inhibits pro-inflammatory actions of leukotrienes
• Decreases edema, mucus secretion, and eosinophil chemotaxis
• Decreases bronchial hyperresponsiveness
• Can produce bronchial relaxation -- still need a short acting Beta2 agonist

In response to Leukotrienes:

• sustained bronchoconstriction
• mucus secretion
• edema in airways

In response to Leukotrienes:

• Contributes to inflammation
• vascular permeability
• tissue fibrosis

• High affinity receptor for LTB4
• Mediates the chemoattraction and proinflammatory actions of LTB4

• Low affinity receptor for LTB4
• Airway hyperreactivity and inflammation

• Hepatitis
• Drug-Drug Interactions

-Can inhibit CYP2C9 (major) and CYP3A4 (minor)

• Well tolerated
• Does not inhibit CYP450 enzymes

Monoclonal Antibody Against IgE

• Prevents crosslinking of IgE on cells associated with allergic response (Mast cells) -- Mast cell degranulation does not occur
• FcεR1 receptor no longer recognizes IgE -- FcεR1 expression is downregulated
• Early phase and late phase of allergic response is prevented

• Generally well tolerated
• Anaphylaxis may occur in patients allergic to hamsters since the antibody is derived from the chinese hamster
• May cause rash, GI symptoms, and decreased platelets counts

Macrolide

• Increases transepithelial resistance through increase tight junction protein expression
• Increases the phagocytosis of apoptotic epithelial cells and neutrophils by macrophages
• Reduces cytokine and chemokine expression
• Modulates mucin gene expression and protein production --> decreased mucus hypersecretion
• Increases expression of defensins

Macrolide

• Increases transepithelial resistance through increase tight junction protein expression
• Increases the phagocytosis of apoptotic epithelial cells and neutrophils by macrophages
• Reduces cytokine and chemokine expression
• Modulates mucin gene expression and protein production --> decreased mucus hypersecretion
• Increases expression of defensins

Macrolide

• Increases transepithelial resistance through increase tight junction protein expression
• Increases the phagocytosis of apoptotic epithelial cells and neutrophils by macrophages
• Reduces cytokine and chemokine expression
• Modulates mucin gene expression and protein production --> decreased mucus hypersecretion
• Increases expression of defensins

COPD

• Neutrophils
• Large increase in macrophages
• Increase in CD8+ T lymphocytes

Asthma

• Eosinophils
• Small increase in macrophages
• Increase in CD4+ Th2 lymphocytes
• Activation of mast cells

COPD

• LTB4
• IL-8
• TNFα

Asthma

• LTD4
• IL-4, IL-5
• TNFα

COPD

• Squamous metaplasia of epithelium
• Parenchymal destruction
• Mucus metaplasia
• Glandular enlargement

Asthma

• Fragile epithelium
• Thickening of basement membrane
• Mucus metaplasia
• Glandular enlargement

α1-Antitrypsin

• this protein is produced by hepatic cells and protects the lungs by blocking the effects of elastases released by neutrophils
• if this protein is not present, these elastases can degrade the alveolar wall elastin

Noxious particles and/or gas

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Reactive oxygen species are generated

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Increased expression of IL-8, LTB4, TNFα

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Recruitment of neutrophils into alveolar tissue

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Increased expression of neutrohil elastase (inactivation of antiproteases through ROS and congenital α1-AT deficiency also result in this)

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Tissue damage

• Antimuscarinics and Muscarinic Receptor Antagonists
• Alpha1-Antitrypsin Replacement Therapy
• Beta2 Agonists
• Corticosteroids (variable effects)
• Combo therapy

Short-Acting Muscarinic Antagonist

• Quaternary amine -- does not penetrate cell membranes that well -- minimal systemic side effects
• Blocks all 5 types of muscarinic receptors -- blockade of M3 is primarily how bronchodilation is produced

Long-Acting Muscarinic Antagonist

• Quaternary amine -- does not penetrate cell membranes that well -- minimal systemic side effects
• Blocks all 5 types of muscarinic receptors -- blockade of M3 is primarily how bronchodilation is produced

• Dry mouth
• Constipation
• Urinary retention
• Tachycardia
• Blurred vision
• Precipitation of narrow-angle glaucoma have been reported

PDE4 Inhibitors

• Increases cAMP -- increased bronchodilation
• Reduced neutrophils by 36% in COPD patients
• Improved lung function slightly, but did not reduce exacerbations or improve quality of life

PDE4 Inhibitors

• Increases cAMP -- increased bronchodilation
• Reduced neutrophils by 36% in COPD patients
• Improved lung function slightly, but did not reduce exacerbations or improve quality of life

PDE4 Inhibitors

• Increases cAMP -- increased bronchodilation
• Reduced neutrophils by 36% in COPD patients
• Improved lung function slightly, but did not reduce exacerbations or improve quality of life

PDE4 Inhibitors

• Increases cAMP -- increased bronchodilation
• Reduced neutrophils by 36% in COPD patients
• Improved lung function slightly, but did not reduce exacerbations or improve quality of life