Environmental Tobacco Smoke and Progesterone Alter Lung Inflammation and Mucous Metaplasia in a Mouse Model of Allergic Airway Disease

  • Valerie L. Mitchell
  • Laura S. Van Winkle
  • Laurel J. Gershwin


The prevalence and severity of asthma is sexually dimorphic. Adult women have a higher incidence of asthma than men. This suggests that this disease may have a hormonal component. Progesterone has been shown to elicit an immune response similar to that seen in allergic asthma and previous studies have shown that progesterone increases total IgE levels in the peripheral blood. In the current study, we examine the effect of environmental tobacco smoke (ETS) and progesterone on hallmarks of asthma pathology in lung tissue with the goal of defining whether progesterone can also exacerbate two key features of airway remodeling: accumulation of eosinophils and increased mucous. We used a mouse model of allergic asthma that includes house dust mite allergen (HDMA). Adult female BALB/c mice were ovariectomized and implanted with time-release progesterone pellets. Mice were housed in filtered air or ETS for 6 weeks (1 mg/m3 total suspended particulate) and exposed to HDMA by inhalation. Progesterone alone did not increase mucous cell mass or the abundance of eosinophils but ETS coupled with progesterone exposure resulted in a significant increase in mucous cell metaplasia and increased accumulation of eosinophils in the asthma model. Levels of cytokines in the bronchoalveolar lavage fluid, measured using a multiplex cytokine assay, revealed elevated levels of both interleukin (IL)-5 and IL-12(p40) in HDMA-exposed animals. The addition of progesterone further exacerbated this response. We conclude that progesterone, in the absence of estrogen, exacerbates airway inflammation and airway remodeling induced by the toxicant ETS.


Environmental tobacco smoke Mouse model of asthma Progesterone 



The authors thank Brian Tarkington, Imelda Espiritu, Marie Suffia, Tammi Harrington, Trenton Combs, and Jackie Chan for their technical expertise as well as Dr. Neil Willits for statistical consultation.


Funding was provided by the California Tobacco-Related Disease Research Program of the University of California, Grant Number 14IT-0081 (to LG), NIH RO1 ES012720 and FAMRI (to LV), and NHBLI #T32 HL007013 (to VM).


  1. 1.
    American Lung Association (2005) Trends in asthma morbidity and mortality. Epidemiology and Statistics Unit, Research and Program ServicesGoogle Scholar
  2. 2.
    Balzar S, Strand M, Rhodes D, Wenzel SE (2007) IgE expression pattern in lung: relation to systemic IgE and asthma phenotypes. J Allergy Clin Immunol 119(4):855–862PubMedCrossRefGoogle Scholar
  3. 3.
    Camancho-Arroyo I, Ruiz A, Gamboa-Dominguez A, Perez-Palacios G, Cerbon M (1994) Immunohistochemical localization of intracellular progesterone and glucocorticoid receptors in the rabbit lung. J Endocrinol 142:311–316CrossRefGoogle Scholar
  4. 4.
    Chen Y, Stewart P, Johansen H, McRae L, Taylor G (2003) Sex difference in hospitalization due to asthma in relation to age. J Clin Epidemiol 56:180–187PubMedCrossRefGoogle Scholar
  5. 5.
    de Marco R, Locatelli F, Sunyer J, Burney P, The European Community Respiratory Health Survey Study Group (2000) Differences in incidence of reported asthma related to age in men and women. A retrospective analysis of the data of the European respiratory health survey. Am J Respir Crit Care Med 162:68–74PubMedGoogle Scholar
  6. 6.
    Deb R, Shakib F, Reid K, Clark H (2007) Major house dust mite allergens Dermatophagoides pteronyssinus 1 and Dermatophagoides farinae 1 degrade and inactivate lung surfactant proteins A and D. J Biol Chem 282(51):36808–36819PubMedCrossRefGoogle Scholar
  7. 7.
    Diaz-Sanchez D, Rumold R, Gong H Jr (2006) Challenge with environmental tobacco smoke exacerbates allergic airway disease in human beings. J Allergy Clin Immunol 118(2):441–446PubMedCrossRefGoogle Scholar
  8. 8.
    Elias JA, Zhu Z, Chupp G, Homer RJ (1999) Airway remodeling in asthma. J Clin Invest 104(8):1001–1006PubMedCrossRefGoogle Scholar
  9. 9.
    Elliot JG, Jensen CM, Mutavdzic S, Lamb JP, Carroll NG, James AL (2004) Aggregations of lymphoid cells in the airways of nonsmokers, smokers, and subjects with asthma. Am J Respir Crit Care Med 169(6):712–718PubMedCrossRefGoogle Scholar
  10. 10.
    Faas M, Bouman A, Moes H, Heineman MJ, Leij LD, Schuiling G (2000) The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertil Steril 74(5):1008–1013PubMedCrossRefGoogle Scholar
  11. 11.
    Flickinger G, Elsner C, Illingworth D, Muechler E, Mikhail G (1977) Estrogen and progesterone receptors in the female genital tract of humans and monkeys. Ann N Y Acad Sci 286:180–189PubMedCrossRefGoogle Scholar
  12. 12.
    Fuchs B, Braun A (2008) Improved mouse models of allergy and allergic asthma—chances beyond ovalbumin. Curr Drug Targets 9(6):495–502PubMedCrossRefGoogle Scholar
  13. 13.
    Gershwin LJ (2007) Effects of allergenic extracts on airway epithelium. Curr Allergy Asthma Rep 7(5):357–362PubMedCrossRefGoogle Scholar
  14. 14.
    Girod S, Zahm J, Plotkowski C, Beck G, Puchelle E (1992) Role of physiochemical properties of mucus in the protection of the respiratory epithelium. Eur Respir J 5(4):477–487PubMedGoogle Scholar
  15. 15.
    Hellings PW, Vandekerckhove P, Claeys R, Billen J, Kasran A, Ceuppens JL (2003) Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma. Clin Exp Allergy 33:1457–1463PubMedCrossRefGoogle Scholar
  16. 16.
    Lange P, Parner J, Prescott E, Ulrik CS, Vestbo J (2001) Exogenous female sex steroid hormones and risk of asthma and asthma-like symptoms: a cross sectional study of the general population. Thorax 56:613–616PubMedCrossRefGoogle Scholar
  17. 17.
    Lemanske RF, Busse WW (2003) 6. Asthma. J Allergy Clin Immunol 111(2, Supplement 2):502–519CrossRefGoogle Scholar
  18. 18.
    Maestrelli P, Saetta M, Mapp CE, Fabbri LM (2001) Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164(10):76S–80SGoogle Scholar
  19. 19.
    Martinez-Moragon E, Plaza V, Serrano J, Picado C, Galdiz JB, Lopez-Vina A, Sanchis J, The Spanish High Risk Asthma Research Group (2004) Near-fatal asthma related to menstruation. J Allergy Clin Immunol 113(2):242–244PubMedCrossRefGoogle Scholar
  20. 20.
    Meek MD (2001) Cigarette smoking and hormone balance in women: new evidence in the anti-smoking campaign. Univ Tor Med J 79(1):8–11Google Scholar
  21. 21.
    Meek MD, Finch GL (1999) Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcription. Environ Res 80(1):9–17PubMedCrossRefGoogle Scholar
  22. 22.
    Middlebrook G (1952) An apparatus for airborne infection of mice. Proc Soc Exp Biol Med 80(1):105–110PubMedGoogle Scholar
  23. 23.
    Miller LA, Hurst SD, Coffman RL, Tyler NK, Stovall MY, Chou DL, Putney LF, Gershwin LJ, Schelegle ES, Plopper CG, Hyde DM (2005) Airway generation-specific differences in the spatial distribution of immune cells and cytokines in allergen-challenged rhesus monkeys. Clin Exp Allergy 35(7):894–906PubMedCrossRefGoogle Scholar
  24. 24.
    Mitchell VL, Gershwin LJ (2007) Progesterone and environmental tobacco smoke act synergistically to exacerbate the development of allergic asthma in a mouse model. Clin Exp Allergy 37(2):276–286PubMedCrossRefGoogle Scholar
  25. 25.
    Moerloose KB, Robays LJ, Maes T, Brusselle GG, Tournoy KG, Joos GF (2006) Cigarette smoke exposure facilitates allergic sensitization in mice. Respir Res 7:49PubMedCrossRefGoogle Scholar
  26. 26.
    Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T, Kuze F (1998) Eosinophilic inflammation in cough variant asthma. Eur Respir J 11(5):1064–1069PubMedCrossRefGoogle Scholar
  27. 27.
    Pauli B, Reid R, Munt P, Wigle R, Forkert L (1989) Influence of the menstrual cycle on airway function in asthmatic and normal subjects. Am Rev Respir Dis 140(2):358–362PubMedCrossRefGoogle Scholar
  28. 28.
    Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD (2006) Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest 116(12):3183–3194PubMedCrossRefGoogle Scholar
  29. 29.
    Redmond AM, James AW, Nolan SH, Self TH (2004) Premenstrual asthma: emphasis on drug therapy options. J Asthma 41(7):687–693PubMedCrossRefGoogle Scholar
  30. 30.
    Rumold R, Jyrala M, Diaz-Sanchez D (2001) Secondhand smoke induces allergic sensitization in mice. J Immunol 167(8):4765–4770PubMedGoogle Scholar
  31. 31.
    Seymour BWP, Friebertshauser KE, Peake JL, Pinkerton KE, Coffman RL, Gershwin LJ (2002) Gender differences in the allergic response of mice neonatally exposed to environmental tobacco smoke. Dev Immunol 9(1):47–54PubMedCrossRefGoogle Scholar
  32. 32.
    Seymour BWP, Pinkerton KE, Friebertshauser KE, Coffman RL, Gershwin LJ (1997) Second-hand smoke is an adjuvant for T Helper-2 responses in a murine model of allergy. J Immunol 159:6169–6175PubMedGoogle Scholar
  33. 33.
    Shao R, Egeciolu E, Weijdegard B, Ljungstrom K, Ling C, Fernandez-Rodriguez J, Billig H (2006) Developmental and hormonal regulation of progesterone receptor A-form expression in female mouse lung in vivo: interaction with glucocorticoid receptors. J Endocrinol 190:857–870PubMedCrossRefGoogle Scholar
  34. 34.
    Skobeloff E, Spivey W, St Clair S, Schoffstall J (1992) The influence of age and sex on asthma admissions. JAMA 268:3437–3440PubMedCrossRefGoogle Scholar
  35. 35.
    Smith MN (2007) Medical encyclopedia: serum progesterone. MedlinePlus, US National Library of Medicine and the National Institutes of HealthGoogle Scholar
  36. 36.
    Stanford KI, Mickleborough TD, Ray S, Lindley MR, Koceja DM, Stager JM (2006) Influence of menstrual cyle phase on pulmonary function in asthmatic athletes. Eur J Appl Physiol 96(6):703–710PubMedCrossRefGoogle Scholar
  37. 37.
    Suda T, Chida K, Hayakawa H, Imokawa S, Iwata M, Nakamura H, Sato A (1999) Development of bronchus-associated lymphoid tissue in chronic hypersensitivity pneumonitis. Chest 115(2):357–363PubMedCrossRefGoogle Scholar
  38. 38.
    Szekeres-Bartho J, Barakonyi A, Par G, Polgar B, Palkovics T, Szereday L (2001) Progesterone as an immunomodulatory molecule. Int Immunopharmacol 1:1037–1048PubMedCrossRefGoogle Scholar
  39. 39.
    Tan K, McFarlane L, Lipworth B (1997) Modulation of airway reactivity and peak flow variability in asthmatics receiving the oral contraceptive pill. Am J Respir Crit Care Med 155:1273–1277PubMedGoogle Scholar
  40. 40.
    Teague SV, Pinkerton KE, Goldsmith M, Gebremichael A, Chang S, Jenkins RA, Moneyhun JH (1994) Sidestream cigarette smoke generation and exposure system for environmental tobacco smoke studies. Inhal Toxicol 6:79–93CrossRefGoogle Scholar
  41. 41.
    Trimble NJ, Botelho FM, Bauer CM, Fattouh R, Stampfli MR (2009) Adjuvant and anti-inflammatory properties of cigarette smoke in murine allergic airway inflammation. Am J Respir Cell Mol Biol 40(1):38–46PubMedCrossRefGoogle Scholar
  42. 42.
    Troisi R, Speizer F, Willett W, Trichopoulos D, Rosner B (1995) Menopause, postmenopausal estrogen preparations and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med 152:1183–1188PubMedGoogle Scholar
  43. 43.
    Van Hove CL, Moerloose K, Maes T, Joos GF, Tournoy KG (2008) Cigarette smoke enhances Th-2 driven airway inflammation and delays inhalational tolerance. Respir Res 9:42PubMedCrossRefGoogle Scholar
  44. 44.
    Van Winkle LS, Evans MJ, Brown CD, Willits NH, Pinkerton KE, Plopper CG (2001) Prior exposure to aged and diluted sidestream cigarette smoke impairs bronchiolar injury and repair. Toxicol Sci 60(1):152–164PubMedCrossRefGoogle Scholar
  45. 45.
    Venn A, Lewis S, Cooper M, Hill J, Britton J (1998) Questionnaire study of effect of sex and age on the prevalence of wheeze and asthma in adolescence. BMJ 316(7149):1945–1946PubMedCrossRefGoogle Scholar
  46. 46.
    Vu Hai MT, Logeat F, Warembourg M, Milgrom E (1977) Hormonal control of progesterone receptors. Ann N Y Acad Sci 286:199–209PubMedCrossRefGoogle Scholar
  47. 47.
    Walter MJ, Kajiwara N, Karanja P, Castro M, Holtzman MJ (2001) Interleukin 12 p40 production by barrier epithelial cells during airway inflammation. J Exp Med 193(3):339–351PubMedCrossRefGoogle Scholar
  48. 48.
    Wood GA, Fata JE, Watson KLM, Khokha R (2007) Circulating hormones and estrous stage predict cellular and stromal remodeling in murine uterus 10.1530/REP-06-0302. Reproduction 133(5):1035–1044PubMedCrossRefGoogle Scholar
  49. 49.
    Yoshimoto T, Wang CR, Yoneto T, Waki S, Sunaga S, Komagata Y, Mitsuyama M, Miyazaki J, Nariuchi H (1998) Reduced T helper 1 responses in IL-12 p40 transgenic mice. J Immunol 160(2):588–594PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Valerie L. Mitchell
    • 1
    • 2
  • Laura S. Van Winkle
    • 2
    • 3
  • Laurel J. Gershwin
    • 1
  1. 1.School of Veterinary Medicine, Department of Pathology, Microbiology, and ImmunologyUniversity of California, DavisDavisUSA
  2. 2.Center for Health and the EnvironmentUniversity of California, DavisDavisUSA
  3. 3.School of Veterinary Medicine, Department of Anatomy, Physiology, and Cell BiologyUniversity of California, DavisDavisUSA

Personalised recommendations