Title:The Role of Mitogen-Activated Protein Kinases in Asthma
Volume: 11
Issue: 2
Author(s): Manzoor M. Khan and Eric B. Patterson
Affiliation:
Keywords:
Asthma, mitogen activated protein kinases, ERK1/2, p38, cytokines, signal transduction, bistability.
Abstract: Asthma is a chronic inflammatory disease of the airways with distinct features including nonspecific airway
hyper-responsiveness, reversible bronchoconstriction, inflammation, and airway remodeling. The classical characteristics
of asthma are the activation and recruitment of inflammatory cells, shedding of bronchial epithelium, subepithelial
fibrosis, angiogenesis, mucus metaplasia and changes in the mass of airway smooth muscle cells. A complex interaction
between environmental and genetic factors contributes to the disease and its heterogeneity. Various cell types, endogenous
mediators including cytokines, chemokines, and growth factors contribute to its pathological events. Eosinophils play a
dominant role in the disease, however, neutrophils also participate in more severe cases. The chronic inflammation and
airway remodeling result from the effects of cytokines on various cell types that participate in the etiology and
pathogenesis of the disease. Cytokines bind to their receptors and through multiple signal transduction mechanisms
produce the effects. Up to 10% of the patients are refractory to current therapy for asthma.
The pathological events in asthma at least in part result from the induction of Mitogen Activated Protein Kinases (MAPK)
and their associated cytoplasmic proteins. The MAPK signaling cascades play an important role in the activation of
inflammatory cells, and are involved in the immune responses and the lymphocyte development. It has been proposed that
the clinical symptoms of asthma are dependent on the immunological as well as tissue based memory resulting in chronic
signaling that produces a bistable state. The bistable state explains the persistence of symptoms of asthma between
episodes. Sustained extracellular regulated kinase 1/2 (ERK1/2) signaling is an example that is responsible for the tissuebased
signaling memory.
The aim of this review to discuss the recent developments in understanding the function of MAPK, ERK1/2 and p38, and
their cytoplasmic proteins in asthma. This will include the role of MAPK pathways in cell types associated with asthma.
Specifically their role in T cells, B cells, macrophages, mast cells, eosinophils, dendritic cells, endothelial cells, epithelial
cells, and airway smooth muscle cells will be discussed and the novel concept of bistability in asthma will be described.
