Asthma is a polyetiologic disease with a complex pathogenesis. Atopy predisposes patients to developing asthma, and a Th2-type immune response plays a dominant role in the pathogenesis of asthma. However, natural asthma exacerbations are frequently triggered by upper respiratory infections, and physical, environmental and emotional stress. Some of the foregoing asthma triggers are likely to stimulate a non-Th2 type immune response and thereby, cause asthma exacerbation. The exact mechanism of asthma exacerbation induced with these diverse triggers is unknown. The main objective of this proposal is to identify a common signaling mechanism that links allergens (Th2 trigger), viral (Th1 trigger) and bacterial (innate trigger) infections-induced asthma exacerbations. Our central hypothesis is that the p38-MK2 signaling pathway links the innate and Th1 immunity to allergic inflammation and thereby, plays an important role in asthma exacerbation. In order to test this hypothesis we will study the role of the p38 MAP kinase and its downstream effector MK2 in induced asthma in a mouse model of multiple allergic sensitivity and chronic exposure. The activation and the role of p38 and MK2 will be examined following challenge of sensitized animals with allergens, virus and bacterial peptidoglycans (TLR2 ligand). The importance of p38 will be examined by pharmacological inhibition as well as by overexpression of a dominant negative mutant. We will examine MK2 knockout mice to establish its biological relevance in asthma. Finally, we will examine the activation of p38 and MK2 in biopsy samples from patients with increasing asthma severity and from control subjects. Our preliminary results suggest that both p38 and MK2 play an essential role in airway inflammation, mucus production, airway hyperreactivity and airway remodeling. Therapeutic interventions targeting the p38-MK2 pathway are likely to prevent asthma exacerbations induced with diverse triggers.
| Christianson, Christina A; Goplen, Nicholas P; Zafar, Iram et al. (2015) Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J Allergy Clin Immunol 136:59-68.e14 |
| Guo, Lei; Chen, Chaoyu; Liang, Qiaoling et al. (2013) Nuclear translocation of MEK1 triggers a complex T cell response through the corepressor silencing mediator of retinoid and thyroid hormone receptor. J Immunol 190:159-67 |
| Alam, Rafeul (2013) Conditions mimicking asthma. Foreword. Immunol Allergy Clin North Am 33:ix-x |
| Hanifi, Arezoo; Goplen, Nicholas; Matin, Mohammad et al. (2012) A linear parametric approach for analysis of mouse respiratory impedance. IEEE Trans Biomed Circuits Syst 6:287-94 |
| Goplen, Nicholas; Karim, Zunayet; Guo, Lei et al. (2012) ERK1 is important for Th2 differentiation and development of experimental asthma. FASEB J 26:1934-45 |
| Ostroukhova, Marina; Goplen, Nicholas; Karim, Md Zunayet et al. (2012) The role of low-level lactate production in airway inflammation in asthma. Am J Physiol Lung Cell Mol Physiol 302:L300-7 |
| Tundwal, Kavita; Alam, Rafeul (2012) JAK and Src tyrosine kinase signaling in asthma. Front Biosci (Landmark Ed) 17:2107-21 |
| Alam, R; Gorska, M M (2011) Mitogen-activated protein kinase signalling and ERK1/2 bistability in asthma. Clin Exp Allergy 41:149-59 |
| Alam, Rafeul (2011) Foreword: the stress of writing about stress. Immunol Allergy Clin North Am 31:xi-xii |
| Alam, Rafeul (2010) Foreword. Atopic dermatitis. Immunol Allergy Clin North Am 30:xiii-xiv |
Showing the most recent 10 out of 28 publications
