ASTHMA AND AIR POLLUTIONDanny Ting Hong Liu, Derick Oduro, Antony Choi, Jakov Krezic

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

The Afflicted

Children under 19 Higher exposure to heavier particulate matter More sensitive immune system Higher Respiratory Load Narrow Airways/Developing Lungs Oral Breathers (No nasal filter)

Air Pollution and Asthma Statistics 21,000 Canadians die prematurely to

air pollution vs 2400 from traffic accidents

Asthma affects at least 13% of children in Canada

Asthma incidences has increased by 30% between 1996 and 2005

*Based on stats from 2008

Pollution and Risk Factors

Genetics

Traffic Related Air Pollution Gases Particulate Matter

Residual Oil Fly Ash (ROFA) Diesel Exhaust (DEP)

Glutathione-S-Transferase (GST)

GST plays an important role in antioxidant defenses Oxidative stress thought to be involved with

development and severity of asthma Down-regulation is found in children with asthma GSTP1 Ile105Val genotype

Found to have significantly lower GST activity GSTM1-null children with asthma

Decreased lung function associated with ozone exposure

NFE2L2 - factor that activates antioxidant pathways Protect macrophages and epithelial cells from DEP

TNF-α

Cell signaling protein involved in systemic inflammation Regulation of immune cells, induction of

fever, effects apoptosis, induces inflammation

Dysregulation found implicated with several inflammatory conditions (including asthma)

Increased expression found in airways of patients with asthma

TNF-α -308 GA genotype (~14% population) Found to be related to higher inflammatory

activity

Tying Genetics to Air Pollution The inflammatory response after

exposure to air pollutants is more prominent in those with GSTP1 Ile105Val TNF-α -308 GA genotypes

Gases

Ozone activates TLR4

Gases

ROS, RNS and Ozone activates NF-kB and AP1 NF-kB: controls many

of the inflammatory genes

AP-1: controls inflammatory and Glutathione synthesis

Glutathionylation

Gases

GSH depletion in vivo leads to inhibition of Th1 and production of Th2 IFN gamma inhibited IL-4 promoted

GSH depletion also activates apoptosis cascades BAX binds to

mitochondrial wallreleasing apoptogenic factors

ROFA Composition

Residual Oil Fly Ash comes from oil combustion. Sulfates Nitrogen Carbon Aromatic compounds /Hydrocarbons Heavy metals.

ROFA

Chelation experiments show significant effect from ROFA is due to metals, especially vanadium

Enhance allergen induced pulmonary allergic response

Suppress TLR4 degradation

ROFA Immunologic Response ROFA's act on dendritic cells gene

expression of IL-12p70 and by causing overproduction of interleukins and cytokines.

Cytokines cause the recruitment of TH1 and TH2 cells which also release cytokines and interleukins.

This causes inflammation by creating an influx of eosinophils and other WBC.

ROFA Immunologic Response (Cont.) Normal Inflammation Responses would

be modulated by T reg cells. Patients exposed to ROFAs show lower

activity of T reg cells by reduced expression of PDL-1 (in D cell)

Hypermethylation at Locus FOXP3 in T Reg proteins lowers viability.

TLR4 Allergic Response

Receptor responsible for immunologic response of body to lipopolysaccharides (in ROFA and gram negative bacteria)

Cells exposed to ROFAs show higher expression of TLR4 receptors and less degradation.

TLR4 Degradation Inhibition

Vanadate acts as a tyrosine phosphatase inhibitor Structural mimic of a phosphate group

Prevents dephosphorylation of Hsr Key Component in Clathrin-coated

endosomes Decreases size of endosomes for TLR4

degradation

TLR4 Degradation Inhibition

PDB Model: Tyrosine Phosphatase bound to Vanadate (2I42)

Red: HydrophobicWhite: HydrophilicGreen: Vanadate

Diesel Exhaust Particles

Composition PAH adsorbed to a carbon core Metals

Triggers Type 2 Helper T cell immunity Can activate Aryl Hydrocarbon Receptor

(AhR)

Aryl Hydrocarbon Receptor (AhR)

First heterodimerizes with ARNT then binds DRE (induces CyPs)

Cytokine activation (TGF-a, TNF-a, MMP) Production of Prostaglandins through Cyclooxygenase

PGE2 – activate mucin production PGD2 – induce chemotaxis of Th2 cells, eosinophils,

basophils (inflammatory response) May activate NF-kB Activation inhibits gamma catenin which links E-

cadherin to actin filaments. Reduces ability of epithelial cells to act as a barrier and increases allergic response

Aryl Hydrocarbon Receptor (AhR)

(Chiba et al, 2011)

Pharmacy Context

Reducing air pollution exposure to children is hard

Redox based Antioxidant supplements2

Vitamin C Vitamin E

Pollution in Canada

(Environment Canada, 2015)

Plans for Pollution

(Environment Canada, 2015)

Summary

Genes affected are: GSTP1, GSTM1, NFE2L2 and TNF alpha Ozone can activate both TLR4 and TNF-R NF-kB and AP-1 are sensitive to ROS and RNS and

upregulate immune response after deglutathionylation Vanadate mimics phosphate to block tyrosine phosphatase

keeps Hrs phosphorylated decrease endosomal fusion decrease TLR4 degradation

ROFAs activate TH2 and TH1 responses by regulating cytokine and interleukins expression in dendritic cells. Treg Proteins are inactive in asthma patients which causes prolong response.

AhR activates NF-kB, prostaglandins (D and E) and inhibits gamma catenin (breaking E-cadherin)

References

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References

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References

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References

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