Air pollution – mechanisms of action of main air born irritants

1. Air pollution – mechanisms of action of main airborn irritants Assoc. Professor Jana Plevkova, MD, PhD, 2011

3. Respiratory system It s open system in permanent contact with atmospheric air, and all components it comprises by every breath someone takes Physiological components of atmospheric air are oxygen, nitrogen, carbon dioxide, water vapors and some inert gases – other than these are considered as being pollutants It is well known and defined relationship between particular airborn irritants and airway diseases cigarette smoke – cancer, chronic bronchitis alergenes – bronhcial asthma, hyperreactivity particles of minerals – pneumoconiosis mikroorganisms – infectious diseases physical properties of inhaled air – temperature, humidity

4. Defensive and protective airway mehanisms protective – they prevent pollutants from entry to the airways defensive – they try to eliminate noxas and mucus out of the airways reflex & nereflex mechanisms breathing pattern changes warm/humidity countercurrent apnoic reflex filtration of particles sneezing Waldayer ly filter sniffing airways fluids with AM prop. exspiration reflex MCT cough immunocompetent cells bronchoconstriction proteases/antiproteases oxidants/antioxidants

5. Historically recognized episodes of air pollution Meuse Valley in Belgium in 1930 Donnora, Pensylvania USA 1948 London 1948 In the past, most of the air born pollutants, mainly sulfur oxides were products of coal combustion (for heating purposes) in private houses Recognized bad impacts on human health pushed government in GB to establishment of regulations in the force to decrease air pollution – so they established „Clean Air Act“ in 1956 – the consequence was switch from coal heating to gas heating, thus reducing negative impact on human health

7. Main sources of outdoor pollution - combustion of fossile fuels - traffic – lots of cars, crowded in cities - industry – mainly petrochemical and metalurgical industry - volacnic erruptions, forrest wildfires Lets say – these are molecules coming mainly fromtraffic and industry and they influence pupulation of particular region

8. Main sources of indoor pollution There had been identified more than 300 volatile substances in the buildings – considered as being indoor pullutants they come from building materials stains, panitings cleaners, fumes cigarette smoke In the 1980 „sick building syndrome“ had been described – its defined as onset and progression of any symptoms and signs induced by the stay in these „polluted – contamind“ spaces with increased concentration of indoor pollutants (headache, weakness, fatigue, dizziness, nausea) Presence of considerable concentration of indoor polutants is usually underestimated. The evidence could be growing incidence of occupational respiratory diseases.

10. Classification of air born pollutants based od physical and chemical properties 1. gases ( example: O3, NO2, SO2, CO) 2. vapors, fumes, aerosols – chlorine, CdO, acid aerosols 3. anorganic particles – niclkel, asbestos, sillicon - compounds 4. oranic particles (polleen, cirn dust, benzpyren) 5. radioactive gases (radon) and radionuclides 6. mixtures – cigarette smoke, diesel engines exhalates

11. Impact on humanhealth Final impact of air born irritants depends on atmosphere, which significantly change properties of pollutants Important is also humidity, sun shine (photoeffect), presence of different microparticles in the atmosphere, which may turn primary pollutants into secondary pollutants, some of them are even more toxic The question is – if they are so heterogenic with different chemical properties, how do they influence airways? Why do they induce similar symptoms? And have similar effects? TRPA1 channel – expressed on afferent nervesin airways . Is relevant for majority of air born pollutants, they activate the channel by covalent modification of the AA on the N terminus of the molecule Activation of TRPA1 induces the sensation of airway irritation, chest tightness, urge to cough, may interfere with pathogenesis of inflammatory processes through neurogenic inflammation

12. Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735846/figure/F1/

13. Typesofairpollution London type - historic term describing air pollution in London in 50 ´s - sulphur oxides, aerosols of sulphuric acid and particular salts, particles from combustion of fossile fuels, mainly coal Annualmeanpollution in London, 1958-1974

15. Los - angeles type - Primary source for this kind of pollution is traffic a lots of cars in cities, crowded and busy traffic – produced pollutants are mainly nitrogen oxides and aromatic carbohydrates Sun shine – (UV component) is critical for the creation of secondary compounds, pollutans, with increased toxic capabilities like ozone, aldehydes, ketones, peroxyacylnitrites

16. Air quality index

17. Entrance of the pollutants to the body At rest and mild physical exercise humans preffere nasal breathing turbulent airflow counter current heat/moisture exchange impaction and filtration of corpuscular pollutants dilution of gases Pharmacokinetics depends on the solubility and secondary chemical processes in the superficial fluid layer, and also on capabilities of pollutants for difusion Deposition of corpuscular pollutants depends on aerodynamic diameter, Larger particles are trapped within the upper airways, while smaller penetrate deeper to the airways

18. Pollutants may initiate protective and defensive reflexes (sneezing, coughing, urge to cough, sensation of airway irritation, dyspnoe, chest tightness High concentration of irritants may induce overproduction of mucus with altered chemical properties (viscosity) and dysregulation of cilliary movemement – leading to disturbances of MCT The result might be stagnation of the mucus, obliteration of small diameter airways, with possible growth of bacteria In case that pollutants hit the alveolar system it may lead to activation of alveolar macrophages, which induce inflammytory and fibrotic response of the lung tissue Activation of proteases, oxidative stress – direct damage to the lung tissue

19. Toxicinfluences Sulphur dioxide SO2 is completely resorbed in the nasal cavity and upper airways In peripheral airways it may work in transformed form, absorbed on particles, or in form of acid aerosol, and it may slow down or completelly stop MCT Irritation of the vagus nerve terminals may lead to bronchoconstriction In case of repeated exposition to lower concentrations – chronic inflammatory changes might be induced by activation of proteolytic enzymes, mediators and reactive oxygen species released from inflammatory cells

20. Ozone Represents appx 50% of all oxidizing substances In case of nasal breathing 80% of ozone is absorbed in upper airways Deep breathing, or oral breathing may bring ozone deeper to the lungs Acute exposure induces inflammatory changes with PMN infiltration and epithelial shedding Longer exposition may increase permeability of airway epithelium It contributes significantly to airway hyperreactivity

21. Nitrogenoxides Important environmental pollutant, but also indoor in case of gas operating owens or cookers Easily penetrates to the peripheral airways Decreases resistance agianst bacteria, and may damage alveolar macrophages In combination with O3 a SO2 enhances bronchoconstrictory reaction in asthmatics

22. Mechanisms of action Production of reactive oxygen species in the tissues – oxidative stress, with direct damages to the membranes, peroxidation Oxidants react with molecules present in the superficial musocal fluid (unsaturated fatty acids, cholesterol, tryptophane and other) with production of ROS, aldehydes and peroxides Release of chemotactic factors – attraction of immunocompetent cells Oxidative stress causes lipid peroxidation thus increasing permeability of cell membranes

23. Diesel engines The most important souce for PM10 Corpuscular pollutants are danagerous because they are capable to prolong the contact of any other pollutans absorbed to them, attached to them with the mucosa – allergenes for example. Interaction of PM10 & polleen grain – release of specific proteines - submicroscopic allergenes

24. The role in pathogenesis of airway diseases Morbidity & mortality – in case of respiratory and cardiovascular diseases we can see an increase of them, mainly due to unpleasant weather conditions The rise correlates with the rise of O3 & SO2 Pollutants are being considered the risk factors for chronic respiratory diseases

25. London in the winter 1962

26. RADS – reactive airway dysfunction syndrom Brooks described consequences of acute exposure to air born irritants as an onset of symptoms similar to asthma in predisposed individuals cough, wheezing, irritation of airways, chest tightness in the interval up to , tlak na hrudi a dýchavice do 24 hodín po expozícii iritanto hours after irritant exposure lung function test may reveal limitation of exspiratory airflow positive methacholine provocation test The most common causes for RADS are gases solubile in watter with drop of pH (sulphur and nitrogen oxides), which have same time high oxidizing potential, formaldehyde, paraformaldehyde, isocyanates, organic volatile substances, chemicals for desinfection – mainly with chlorine, and many other

27. Relationship between airway diseases and pollutants Astma a alergies, chronic respiratory diseases Risk factors a) Irritation of mucosa may lead to airway hyperreactivity (neurogenic inflammation) b) Toxic effects on epithelium – increase of its permeability for inhaled aerosols, alergenes, and disturbances of MCT – all of these may lead to longer exposure to allergenes without appropriate airway cleaning excerbation of asthma, COPD, occupational diseases

28. Neurogenicinflammation • Pollutants/irritants stimulate airway nerves via ion channels such are TRP channels, or acid sensing channels – nerves – mainly C fibers share afferent information to the central nervous system, but same time, they can release neuropeptides – neurokinin A, neurokinin B, Substance P, CGRP, VIP and many other. • These neuropeptides could further stimulate nerves around, and also have proinflammatory potential – they can induce vasodilatation, constriction of bronchial smooth musles, increase glandular activity, increase epithelial permeability • Ongoing chronic inflammation in ariways – even at subclinical level – may lead to airway hyperreactivity

29. TRPA1 relevant molecules induce neurogenic inflammation

30. Anexampleforcigarettesmokeinducedlungdamageviaactivatedmacrophages & neutrophils, withreeaseofproteases, matrixmetaloproteasesMMPs – leading to COPD

32. Pathophysiologyofageing, terminalstates and dying

34. Ageing Aging is gradual process of the progressive decrease of vitality, increase of vulnerability of tissues, leading to death It is a process which is mandatory for every living creature, from the very begining of its existence Speaking in medical terms - it is a complex of somatic changes since the end of the growing and maturation phase till the death of the organism Same time the organism is undergoing aging processes, we can say, there is increased incidence of diseases, so it is difficult to say, which changes are due to aging only, and which are due to associated diseases

35. WHO – categories - Middleage: (45 - 59 yrs) - Pre senium: (60 - 74 yrs) - Senium (old): (75 - 89 yrs) - Veryold more than 90 yrs

36. Populationisaging increased and improved quality of life in senior categories better diagnostic options and treatment of diseases which were fatal before

37. 100 50 0 1980 1930 1900 1840 % survivors 0 20 40 60 80 100 age in years

38. Mortality in 80-89 yrs interval within 1950-1995 Japan France Sweden U.K. U.S.A.

39. 1. Rise of mortality with age 2. Changes of biochemical processes 3. Progressive weakness of physiological functions 4. Decreased ability of adaptation Main characteristicsofageing 5. Increased susceptibility to many diseases

40. Somaticchangesduringageing • At the cellular level - the number of postmitotic cells declines, and cells which are still capable of mitosis decrease their activity • At the tissue level – disturbance of the tissue structure, increase of the cells volume whereas their count is reduced, decrease of the ellastine content, increased accumulation of „altered“ colagene, thickness of IST – limitation in oxygen and substrate supply

41. Organ changes • Myocardium – hypertrophy & fibrosis, disturbances of valves, decrease of CO • Vessels – increased rigidity of arteries due to disturbed ratio between collagen and eelsticfibres, deposition of calcium + ATS leads to increased periheral resistance – rise of BP • Blood – anaemia die to decreased Fe reabsorbtion, rise of RBC sedimentation, decrease count and activity of WBC, increased tendency to blood clotting due to changed PLT properties • Kidneys – decrease of GF & Q in kidneys, creatinin not increased, bc of muscle atrophy (no much sources for creatinin) • Respiratory system – decreased compliance, VC, worse diffusion properties, attenuated defensive reflexes + MCT – increased risk for respir, infections

42. Organ changes Git –dysphagia, hiatal hernia, diverticulosis, reduced motility, digestion and reabsorbtion of nutrients, liver atrophy with decreased functions Endocrinne system – decrease of STH, changes of FSH LH after menopause, decrease of T3, decreased glucose tolerance, fibrosis and sclerosis of B cells Skelet and muscles – atrophy for both, decreased ablitities for cartilage regeneration Skin – atrophy & decreased regeneration capabilities of epidermis, wrinkles due to lack of ellastic structures and decreased amount of subcutaneous fatty tissue, grey hair due to decreased melanin synthesis NS – neuronal atrophy, inadequate supply by oxygen and substrates, disturbanced of brain main arteries,, NS – neuropathy Decreased abilities of senses Metabolism – decreased speed, decreased production of heat

43. Theories of ageing systematic punishment of tissues at molecular, cellular, and finally organ level 1. Nutrishment immediatelly after the birts influences duration of life 2. Accumulation of somatic mutations – correlation between ability to repair damaged DNA and duration of the life 3. Increased exposure to stress factors may lead to premature ageing 4. As the age goes, there is an accumulation of toxic metabolic products - peroxides & ROS, glycation of macromolecules • Decreased ability of antioxidant and reparative processes – • leading to accumulation of potentially „ bad“ molecules

44. Geneticfactors all species have geneticly determined duration of life, & its more or less constant number of mitotic processes in particular cells is limited defect synthesis of proteins – gene products due to increased number of somatic mutations same time, reparation of DNA is limited ageing genes – indirect evidences

45. Lessons we have learned from disorders such Wislons´s syndrom or progeriasuggest that aging is multifactorial process based on genetics. We also have information for longevity subjects.

46. Immunefactors Increased number of somatic mutations induces changes of expression of surface antigenes – thus IS is not able to recognize them – and takes them as strangers Whereas immunity decreases with age, activity of autoimmune processes is on rise We can see increased production and release of cytokines – mainly Il1, Il6, TNF Increased amount of growth factors - TGF , IGF, bFGF – those may contribute to unregulated overproduction of extracellular matrix and amyloid deposition to the organs, and vessels – progression of fibrotic changes

49. genetic predisposition diseases & tissue damage healthy food inflammation accumulation of cell deffects healthy life style štýl random changes at the level of macromolecules environmental pollution, smoking food, toxins, conservants stress, oxidation stress

50. TERMINAL STATES (TS) Tanathology: describing mechanism of dying, which lead to irreversible desintegration of organism 1. Preagonal stage: interaction of 2 antagonistic efforts • One leading to the dezintegration of the organism due • to pathological processess (hypoxia, acidosis, hypoperfusion) b) Second represent defensive and compensatory mechanisms (tachypnoe, tachycardia, vasoconstriction, hypertension) • Exhaustion of compensatory reactions leads to  • preterminal apnoe, lack of EEG activity, AV blocks with preautomatic pause, hypotension and tissue hypoperfusion