The Oxygen Model of Asthma – Majid Ali, M.D.

A Clinical Outcome With Integrated Management Plan

Majid Ali, M.D.

(First published in Townsend Letter in 2006*)

In this column, we look at the problems of the etiology and management of bronchial asthma through the prism of oxygen homeostasis. We briefly discuss the dysox model of asthma and present clinical outcome data concerning 24 unselected patients with bronchial asthma who followed — partially in most instances — our non-drug therapies for a period of one year. The readers are referred to Integrative Immunology, the fourth volume of The Principles and Practice of Integrative Medicine1 for an in-depth discussion of the dysox model of allergic and environmental illnesses, as well as for detailed and specific information about nutrient, herbal, oxystatic, and self-regulatory therapies included in our management plans. Specifically, the following were the major components of those programs for the prevention and control of asthma attacks: (1) immunotherapy for IgE-mediated mold and other forms of inhalant allergy; (2) nutritional and herbal therapies for addressing issues of the bowel, blood, and liver ecosystems; (3) direct and indirect oxystatic therapies for the optimization of oxygen homeostasis; and (4) training for effective methods of autoregulation for dissipating effects of chronic anger and resentment.2

IgE antibodies with specificity for mold, mite, and epidermal antigens were detected with a previously described micro-elisa assay3 in the sera of all of our patients with bronchial asthma. From prior experience with patients with asthma, we knew that effective desensitization with antigen immunotherapy administered concurrently with nutrient, herbal, and self-regulatory therapies was essential for good long-term clinical results. Therefore, all 24 subjects in this study received such immunotherapy. As in our past studies of asthma,4 we found that the clinical results were far superior when other relevant issues — altered bowel flora with accompanying mycotoxicosis, impaired hepatic detoxification pathways, toxic metal load, and others — were addressed. The clinical outcome data for 24 patients with asthma (with four patients on steroid therapy prior to initiating the program) are presented in tables 1,2, and 3.

The incidence of asthma in various populations is rising at alarming rates.5 In some sections of Harlem in New York City, 40% of children carry inhalers to school. In a larger sense, the asthma incidence statistics cannot be understood nor asthma effectively prevented and managed without considering the global ecologic changes. Human external and internal ecosystems are under increasing oxidative stress. The oxidizing capacity of the planet Earth is increasing6 The ozone layer is thinning and is oxidizing.7 Global anoxia is increasing and is oxidizing.8 Ever-increasing levels of fossil fuel burning is increasing oxidative stress. Industrial pollution is increasing, and most pollutants are oxidizing. The greenhouse effect is oxidizing. Ten thousand years ago the estimated average temperature of Earth was 50 degrees Fahrenheit,9 and it has been steadily rising. From January to July 1998, average temperatures consistently broke previous monthly records, with temperatures rising to 124 degrees Fahrenheit in India and claiming 3,000 lives.10 The total oxidizing burden of the above natural and anthropogenic elements on human ecosystems has increased enormously in recent decades.

In 2000, one of the authors (MA) presented the oxidative-dysoxygenative model of allergy and hypersensitivity in Current Opinion in Otolaryngology.11 That model of atopy is a unifying model that integrates diverse clinical, biochemical, morphologic, and experimental observations in the following three areas: (1) classical studies of IgE-mediated atopic response and, to a lesser degree, the other three types of Gell and Coombs hypersensitivity responses; (2) an ecologic view of clinical allergy that includes sensitivity to environmental agents independent of the dose of the excitant; (3) an expanded, integrative perspective of hypersensitivity responses that focuses on oxidative-dysoxygenative dysfunction, which profoundly influences sensitivity reactions included in the first two categories. In 2000, one of the authors (MA) also proposed that oxidative coagulopathy is a major pathogenetic mechanism of hypersensitivity disorders in an article published in Environmental Management and Health.12 Our focus in the management of asthma patients was on elements in the bowel, blood, and liver ecosystems that cumulatively add to the total oxidative stress and eventually disrupt cellular energetics. The existence of the dysox state impaired oxygen homeostasis with respiratory-to-fermentative shift was documented by establishing increased urinary excretion of metabolites of Krebs cycle and gkycolytic pathways. This subject is discussed at length in I Dysoxygenosis and Oxystatic Therapies, the third volume of The Principles and Practice of Integrative Medicine.13

Particulate Matter (PM), Diesel exhaust particles (DEP) , Pollutants, and Hypersensitivity

The issues of particulate matter (PM), industrial pollutants, and hypersensitivity are crucial in both understanding the pathogenesis of asthma and for designing rational plans for the prevention and treatment of asthma. PM in ambient air inflicts oxidative injury and induces inflammation in microecologic cellular and organ-system macroecologic systems. Such injury involves myriad prooxidant and proinflammatory pathways, as well as antioxidant and antiinflammatory systems.14-22 Examples of the former include cellular heme oxygenase-1 (HO-1), NADPH cytochrome P-450 reductase (P-450 reductase), nitric synthase, sulfates, nitrates, organic hydrocarbons, metallic compounds, and prooxidant transition metals, such as copper, vanadium, chromium, nickel, cobalt, and iron. The counteractive antioxidant and antiinflammatory responses evoked include superoxide dismutase, catalase, glutathione peroxidase, and antioxidants.

The redox phemonena occurring in the pulmonary and cardiovascular system in patients with asthma have been investigated.23,24 The uptake of PM in macrophages and epithelial cells and induction of oxidative stress is affected by differences in the size of particles — characterized as coarse particles (2.5-10 microns), fine particles (< 2.5 microns), and ultrafine particles (UFP, < 0.1 micron) — and composition of such matter. UFPs are the most potent inducer of cellular heme oxygenase-1 (HO-1) expression and depletion of intracellular glutathione. Furthermore, HO-1 expression is directly correlated with the high organic carbon and polycyclic aromatic hydrocarbon (PAH) content of UFPs.22 What increases the biological potency to UFPs markedly is their localization in mitochondria.33

Diesel exhaust particles (DEP) in ambient air contain redox cycling organic chemicals with potent prooxidative and proinflammatory responses. Such effects are associated with a documented increase in the production of over thirty proteins—a number that will definitely increase with time. Technologies in current use for such studies include matrix-assisted laser desorption/ ionization-time of flight mass spectrometry and electrospray ionization liquid chromatography-mass spectrometry. In doses ranging from 10-100 ìg/ml, organic DEP extracts induce incremental impairment of cellular glutathione systems. A decline in the ratio between glutathione and oxidized glutathione (GSH/GSSG ratio) occurs in parallel with a linear increase in newly expressed proteins. Other antioxidant enzymes and proteins produced in response to DEP (in addition to the above-mentioned heme oxygenase-1) are catalase, proinflammatory components (p38MAPK and Rel A), and products of intermediary metabolism regulated by oxidative stress. At DEP extract doses of over 50 ìg/ml, a steep decline in cellular viability has been documented.25

The biologic effects of PM and DEP are inhibited by a variety of antioxidants and antioxidant enzyme systems, including N-acetylcysteine (NAC), superoxide dismutase (SOD), and others, by a variety of mechanisms.26-28 For instance, N-acetylcysteine (NAC), which directly complexes to electrophilic DEP chemicals, suppresses DEP-induced effects. Not unexpectedly, such responses to pollutants also evoke responses from certain oxidant-generating enzymes, such as NADPH cytochrome P-450 reductase (P-450 reductase), which has been detected mainly in ciliated cells in the respiratory passages. By contrast, CuZn-SOD and Mn-SOD have also been found in the airway epithelium. Another important system induced by DEP is constitutive NO synthase (cNOS) in the airway epithelium and inducible NO synthase (iNOS) in the macrophages. Pretreatment with NG-monomethyl-L-arginine, a nonspecific inhibitor of NO synthase, significantly decreases DEP-induced bronchial hyper-responsiveness.

The increasing amounts of minerals generally increase the degree of oxidative stress in biologic systems. This issue has also been examined in the case of PM- and DEP-induced responses. For instance, the degree of chemiluminescence — an indicator of oxidative stress—shows a strong association between such stress and the amounts of iron, manganese, copper, and zinc in the lung and with iron, aluminum, silicon, and titanium in the heart. 29

In a recent issue, Science reported that particulate matter is estimated to kill more than 500,000 people each year.36 These numbers become even more significant once one realizes that one of every four children in New York City carries an inhaler to school? PM comprises solid and liquid particles derived from industrial and vehicular exhaust, smokestacks, forest fires, windblown soil, road dust, volcanic emissions, and sea spray. Ultrafine particulates are largely derived from combustion of fossil fuel and have a core of elemental carbon coated with layers of chemicals, such as sulfates, nitrates, organic hydrocarbons, and metallic compounds.

The pro-oxidative/pro-inflammatory effects of many components of PM are well established. Organic hydrocarbons, including polycyclic aromatic hydrocarbons, quinones, and transition metals (copper, vanadium, chromium, nickel, cobalt, and iron) also play a role.35 PM serves as a template for electron transfer to molecular oxygen in redox cycling events involved in the above. Additional oxyradicals are also produced in target cells (bronchial epithelial cells, macrophages, and others) when in contacted with PM. Of special interest in this context are oxyradicals produced in response to particle uptake by biologically catalyzed redox reactions in the matrix, biomembranes, and mitochondria.22 The oxyradical-inflicted damage includes that affecting: (1) cellular proteins (especially those involved in intracellular signaling cascades); (2) lipids; (3) complex sugars; (4) DNA; (5) molecular species of epigenetic regulatory mechanisms; (6) cytokines and transcription factors, such as NFk-B49 and eventually cytokine and cytokine genes.37 These products are produced locally in target tissues as well as systemically and lead to widespread pro-inflammatory effects remote from the site of damage.

Clinical Outcome With Integrative Therapies

All integrative management plans for subjects in this open clinical outcome study were designed according to the needs of the individual patients as determined by at least two physicians involved in the care on clinical grounds. The general guidelines about the use of redox-restorative and oxystatic therapies are given in Table 4. As for bowel ecology, we prescribed probiotics regularly and antifungals when overgrowth of oxyphobes was suspected on clinical grounds. We liberally prescribed phytofactor formulations comprising echinacea, astragalus, burdock root, goldenseal, pau D’arco, turmeric, and cloves. It might be added that the cytokine activities of several of those phytofactors have been extensively documented.38-40 Evidence for efficacy of various nutrients for asthma has been published in others studies.40-42 The compositions of the intramuscular and intravenous protocols employed in this study and the guidelines for their use have been described in Integrative Nutritional Medicine, the fifth of The Principles and Practice of Integrative Medicine.2

We wish to point out that several patients in the study were unable to receive prescribed intravenous and intramuscular therapies for reasons of non-reimbursement from their insurance carriers. Notwithstanding, there was a dramatic reduction in the number of emergency department visits for control of asthma attacks during the period of treatment (4 visits during the year of treatment vs. 27 visits during the year before beginning the program, Table 1). There was an equally dramatic reduction in the need for antibiotics for various infections during the period of the study (38 vs 5). It is noteworthy that many episodes of infections were successfully managed without antibiotics (17 infections out of a total of 22).

Table 1. Intensity of Care During 12-Months Periods Before and During Integrative Management Plan Based on the Dysox Model of Asthma in 24 Patients



Visits to Hospitals



Viral/bacterial infections



Frequency of Antibiotics Use



Table 2. Reduction in the Use of Drug Therapies for Asthma During 12-Months Periods Before and During Integrative Management Plan in 24 Patients















The data concerning the reduction in the use of bronchodilator drugs and steroids with integrative plans are also noteworthy (Table 2.) We were able to discontinue steroid therapy in five of 11 patients who were receiving such therapy prior to their care at the Institute. The data in Table 3 validate the clinical observations of practitioners of integrative medicine concerning the general benefits of integrative therapies administered for putatively ‘specific’ disorders, such as bronchial asthma. This is a crucially important issue from the standpoint of the comparative benefits of pharmacologic agents that block specific mediators of inflammatory and healing responses — nearly always causing serious adverse effects — and restorative nutrients, phytofactors, oxystatic therapies, and self-regulatory methods that enhance physiologic healing responses.

Table 3. Overall Clinical Response During 12-Months Periods Before and During Integrative Management Plan in 24 Patients With Asthma





General health










In closing, the main message of this column is this: the majority of patients with bronchial asthma treated with various classes of asthma drugs (including steroids) can be effectively managed without those drugs and with integrated plan based on the dysox model of asthma. Such plans should comprise the following: (1) immunotherapy with mold and other relevant inhalant allergy; (2) restoration of bowel, liver, and blood ecologies with suitable nutrient and phytofactor formulations; (3) direct and indirect oxystatic therapies; and (4) effective methods of autoregulation to dissipate chronic anger and resentment. We believe the reported clinical results would have been substantially improved if therapies, which we employed, were administered in a universal health insurance system that assured medical care without interruption for reasons of costs.

Table 4. General Guidelines for Nutrient and Redox-Restorative Supplements forPatients With Bronchial Asthma With and Without Associated Indolent Immune Disorders

Asthma Associated With Chronic Indolent Immune Dysfunction

Asthma Unassociated With Chronic Indolent

Immune Dysfunction



C, 1,000 to 2,000 mg;

E, 200 to 400 IU;

A, 5,000 to 7,500 IU;

D, 100 to 250 IU;

B-complex, 25-50 mg;

B12, 1,000 mcg weekly for four weeks.


C, 3,000 to 5,000 mg;

E, 400 to 800 IU;

A, 10,000 to 15,000 IU;

D, 100 to 250 IU;

B-complex, 30-50 mg;

B12, 1,000 to 5,000 mcg weekly for four to six weeks .


magnesium, 1,000 to 1,500 mg;

calcium, 750 to 1,000 mg;

potassium, 200 to 400 mg;

chromium, 100-300 mcg;

selenium, 100-300 mcg;

molybdenum, 100-300 mcg.

magnesium, 1,500 to 2,500 mg;

calcium, 1,000 to 1,500 mg;

potassium, 400 to 600 mg;

chromium, 400-600 mcg;

selenium, 400-600 mcg;

molybdenum, 400-600 mcg.

Redox-Restorative Substances

Glutathione, 200-300 mg;

N-acetylcysteine, 200-300 mg; Methylsulfonylmethane, 200 to 500 mg; lipoic acid, 100 to 200 mg; taurine, 500 to 1,000 mg, coenzyme Q10, 30 to 50 mg;

pycnogenol, 50 to 100 mg.

Glutathione, 600-800 mg;

N-acetylcysteine, 600-800 mg; methylsulfonylmethane, 1,000 to 1,500 mg; lipoic acid, 300 to 500 mg; taurine, 1,500 to 2,000 mg, coenzyme Q10, 100 to 150 mg;

pycnogenol, 100 to 150 mg.


1 Ali M. The Principles and Practice of Integrative Medicine Volume IV: Integrative Immunology and Allergy: The Oxidati ve-Dysoxygenative Perspective. 2005. Canary 21 Press,New York. http://www.Canary21press. com

2. Ali M. The Principles and Practice of Integrative Medicine Volume V: Integrative Nutritional Medicine. 2005. Canary 21 Press, New York. http://www.Canary21press. com

3. Ali M & Ramanarayanan MP. A computerized micro-ELISA assay for allergen-specific IgE antibodies. Am J Clin Pathol 1984;81:591.

4. Ali M. Intravenous Nutrient Protocols in Molecular Medicine, 1st edition 1987, 6th printing 2nd Edition 1997. The Institute of Preventive Medicine, Denville, New Jersey.

5. Marwick C. Helping city children control asthma. JAMA. 1997;277:1503-4.

6. Holland HD. The Chemistry of Atmosphere and Oceans. 1978. New York, Wiley.

7. Knoll AH. Breathing room for early animals. Nature 1996;382:111-112.

8. Dwyer JJ, Burnett LE. Acid base status of the oyster Crassostrea virginica in response to air exposure and to infections by Perkinus marinus. Biol Bulletin 1996;190:139-147.

9. Cooper SR, Brush GS. Long-term history of Chesapeake Bay anoxia. Science 1991;254:992-994.

10. Climate And the Rise of Man. U.S.News & World Report, June 8, 1992.

11. Ali Recent advances in integrative allergy care. Current Opinion in Otolaryngology & Head and Neck Surgery 2000;8:260-266.

12. Ali M. Oxidative coagulopathy in environmental illness. Environmental Management and Health. 2000;11:175-191.

13. Ali M. The Principles and Practice of Integrative Medicine Volume III: I Dysoxygenosis and Oxystatic Therapies. 2005. Canary 21 Press, New York.

14. McCunney RJ. Asthma, genes, and air pollution. J Occup Environ Med. 2005 Dec;47(12):1285-91.

15. Kobzik L, Goldsmith CA, Ning YY, et al. Effects of combined ozone and air pollution particle exposure in mice. Res Rep Health Eff Inst. 2001 Dec;(106):5-29; discussion 31-8.

20. Feng JT, Luo BL, Hu CP, et al. Effect of xinglong pingchuan recipe on interleukin-5 and the inflammagen related to oxygen free radical in asthmatic mice. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005 Aug;30(4):437-40.

19. Tsukahara H. Current status of redox markers in immunological and inflammatory diseases. Rinsho Byori. 2005;53(8):759-67.

16. Fujisawa T. Role of oxygen radicals on bronchial asthma. Curr Drug Targets Inflamm Allergy. 2005;4:505-9.

17. Kinnula VL. Production and degradation of oxygen metabolites during inflammatory states in the human lung. Curr Drug Targets Inflamm Allergy. 2005;4:465-70.

18. Kato M, Hayashi Y, Kimura H. Oxygen radicals in inflammation and allergy related to viral infections. Curr Drug Targets Inflamm Allergy. 2005;4:497-501.

21. National Academy of Sciences, National Research Council, Research Priorities for Airborne Particulate Matter: I–Immediate Priorities and a Long-Range Research Portfolio. 1998.National Academy of Sciences, Washington, DC.

22. Li N, Sioutas C, Cho A, et al. Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage. Environ Health Perspect. 2003;111:455-60.

22. Lima H-B, Ichinosea T, Miyabaraa Y, et al. Free Radical Biology and Medicine . 1998;25:635-644.

24. Nel A. Air Pollution-Related Illness: Effects of Particles. Science. 2005;308:804-806.

25. U.N. Environment Program and WHO Report, Environment. 1994;36:4.

26. Gurgueira SA, Lawrence J, Coull B, et al. Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation. Environ Health Perspect. 2002 Aug;110(8):749-55.

27. K. Donaldson, C. L. Tran, Inhal. Toxicol.2002;14,5 (2002)

28. Takizawa H. Diesel exhaust particles and their effect on induced cytokine expression in human bronchial epithelial cells. Curr Opin Allergy Clin Immunol. 2004;4:355-9.

29. Bonvallot V, Baeza-Squiban A, Baulig A, et al. Organic compounds from diesel exhaust particles elicit a proinflammatory response in human airway epithelial cells and induce cytochrome p450 1A1 expression.. Am J Respir Cell Mol Biol. 2001;25:515-21.

30.. Xiao GG, Wang M, Li N, et al. Use of Proteomics to Demonstrate a Hierarchical Oxidative Stress Response to Diesel Exhaust Particle Chemicals in a Macrophage Cell Line. J Biol Chem. 2003;278:50781- 50790.

31. Jang AS, Choi IS, Takizawa H, et al. Additive effect of diesel exhaust particulates and ozone on airway hyperresponsiveness and inflammation in a mouse model of asthma. J Korean Med Sci. 2005 Oct;20(5):759-63.

32. Lee KS, Park HS, Park SJ, et al. A prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid, regulates vascular permeability by reducing vascular endothelial growth factor expression in asthma. Mol Pharmacol. 2005;68:1281-90.

33. Masini E, Bani D, Vannacci A, et al. Reduction of antigen-induced respiratory abnormalities and airway inflammation in sensitized guinea pigs by a superoxide dismutase mimetic. Free Radic Biol Med. 2005;15;39:520-31.

34. Ichiki H, Hoshino T, Kinoshita T, et al. Thioredoxin suppresses airway hyperresponsiveness and airway inflammation in asthma. Biochem Biophys Res Commun. 2005;334:1141-8.

35. Riccioni G, D’Orazio N. The role of selenium, zinc and antioxidant vitamin supplementation in the treatment of bronchial asthma: adjuvant therapy or not? Expert Opin Investig Drugs. 2005;14:1145-55.

36. Nel A. Air pollution-related illness: effects of particles. 2005;308:804-806.

37. Health Effects Institute Perspectives, pubs-perspectives. htm (April 2002 report).

38. Raghavenra H, Diwakr BT, Lokesh BR, et al. Eugenol–the active principle from cloves inhibits 5-lipoxygenase activity and leukotriene-C4 in human PMNL cells. Prostaglandins Leukot Essent Fatty Acids. 2006;4:23-7.

39. Shishodia S, Sethi G, Aggarwal BB. Curcumin: Getting back to the root. Ann N.Y. Acad. 2005;1056:206-217.

40. Druilhe A, Letuve S, Pretolani M. Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis. 2003;8:481-95.

41. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: Antioxidants as a therapeutic strategy. Pharmacol Ther. 2006; February 1.

42. Misso NL, Thompson PJ. Oxidative stress and antioxidant deficiencies in asthma: potential modification by diet. Redox Rep. 2005;10(5):247-55.

Coauthros: Judy Juco, M.D., Alfred Fayemi, M.D. Shara Fischer, B.A., Mahboob Baig, M.B;B.S.

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