AsthMatic Inflammation and Neurocircuitry Activation (MINA) (MINA)

Asthma is characterized by airway inflammation, bronchial hyperresponsiveness and airflow obstruction. The development of symptoms in patients with asthma is initiated by exposure to a variety of airborne substances including aeroallergens. The inhalation of these allergens by asthmatic subjects initiates a series of complex, interactive immune events through activation of cell bound IgE, which serve to further existing airway inflammation, intensify underlying airway hyperresponsiveness and cause airflow obstruction. Although the immune events and processes associated with these reactions are largely localized to the airways themselves, a variety of other factors can contribute to the ongoing allergic response in either an enhancing or inhibitory manner. The regulation and modulation of these inflammatory actions is a key determinant to the eventual severity of asthma.

The initial step in the activation of the allergic airway response is the ability of inhaled allergen to activate IgE molecules on the pulmonary mast cell to release stored mediators and generate synthesis of new products, which can acutely contract airway smooth muscle. The mast cell also is capable of generating a variety of cytokines, which, in turn, can cause persistence and progression of the allergic response by furthering the underlying inflammation. In addition to mast cell activation, inhaled allergens are capable of stimulating resident lymphocytes in the lung. It is proposed that these allergen-responsive lymphocytes belong to a subpopulation of T helper cells (Th2), which are capable of generating a variety of cytokines, i.e. interleukin (IL)-4, IL-5, and IL-13. These Th2 cytokines can activate the local inflammatory response and can also serve to initiate events outside the lung, which can then further promote the persistence of the allergic inflammatory response.

To illustrate the means by which newly generated lung mediators can affect allergic inflammation, investigators have shown that inhaled allergen is associated with enhanced bone marrow generation of eosinophils. This enhanced bone marrow production of eosinophils is associated with bone marrow cell generation of IL-5, which causes terminal differentiation of eosinophils and their release into the circulation. Presumably, these recently generated eosinophils enter the circulation and are recruited to the lung where they may further the development of eosinophilic inflammation and the severity of asthma.

Other factors also influence the development and intensity of the allergic inflammatory response to inhaled allergen. In preliminary studies, the investigators have found that the stress associated with the final examination period in college students will enhance the eosinophilic inflammatory response to inhaled allergen. In addition, the investigators have found that during the final examination period, and independent of an allergen challenge, circulating eosinophils increase. Moreover, Marin and colleagues (2009) studied children with asthma over a two-year period and found that mononuclear cells from children who reported persistent life stress coupled with an acute stressful event produced elevated levels of asthma-promoting cytokines compared to asthmatic children without chronic stress or healthy controls. These findings suggest that the persistent stress associated with an acute stressor may promote allergic inflammatory events and that these processes include regulation of eosinophil numbers and recruitment to the lung.

From these studies, the investigators have evidence to suggest that stress-related events can influence allergic inflammation and, presumably, that these peripheral responses are regulated by central nervous system (CNS) events. Although stress-related events can modulate inflammatory processes, the mechanisms and CNS-site of this activity are poorly understood. It is proposed that areas of the brain are activated by stress and that these areas of activation may represent sites in the CNS that integrate information concerning the internal state of the body and signal the generation of modulating factors in the enhancement or inhibition of the allergic airway inflammation. To visualize these potential sites of CNS activation in asthma, it is possible to use neuroimaging techniques, such as positron emission tomography (PET) or functional magnetic resonance imaging (fMRI). The investigators have completed two prior studies that used fMRI to evaluate the central mechanisms associated with allergic inflammation, and in both studies, the anterior insula was identified as a region activated by asthma-related emotional cues that predicted the subsequent development of airway inflammation (e.g. Rosenkranz, M et al (2005) Proceedings of the National Academy of Science 102, 13319-13324.). In addition, the investigators have completed a study using PET to evaluate the neural mechanisms through which stress along contributes to asthma-related inflammation in individuals with high and low levels of chronic stress. This study corroborated our findings using fMRI, showing involvement of the insula, and also revealed new mechanisms involving IL-1β/IL-17 as a potential pathway linking through which stress-reactivity primes airway inflammation.

In the research described here, these two experimental paradigms will be merged to 1) determine the contribution of the IL-1β/IL-17 pathway in response of emotion neural circuitry provoked by airway inflammation in the absence of bronchoconstriction and 2) to determine the neural mechanisms and impact of acute stress on the airway inflammatory response to whole lung allergen challenge.