Epithelial alarmins as novel targets for treatment of asthma

Asthma is a chronic obstructive airway disease characterised by episodic or chronic breathlessness due to recurrent bronchoconstriction, mucus production, airway inflammation and structural remodelling of the bronchi. Airway hyperresponsiveness (AHR), i.e. the propensity to get a bronchoconstriction in response to stimuli that do not affect healthy individuals, is a key feature of asthma and a distressing condition. One manifestation of AHR is exercise induced bronchoconstriction (EIB), which is considered to occur when rigours breathing dries the airway epithelium, leading to increased tissue osmolarity and activation om mast cells.

Epithelial alarmins interleukin (IL)-33, thymic stromal lymphopoetin (TSLP) and IL-25 are known to participate in the key pathophysiological processes in inflammatory diseases, their role in asthma is not fully elucidated. Using human small bronchi and human lung mast cells in ex vivo experiments, the role of epithelial alarmins in initiating airway hyperresponsiveness was therefore studied with a special focus on mast cell-dependent bronchoconstriction and the release of mast cell mediators.

In Paper I, the human small bronchi were exposed to a combination of IL-33, TSLP and IL-25 and contractile responses were measured. The combination of the cytokines enhanced antigen-induced contractions and increased the release of mast cell mediators’ histamine and prostaglandin (PG)D2, while having no effect on contractions evoked by histamine.

In Paper II, hyperosmolar-induced contractions in human small bronchi were studied, with the aim to further investigate the role of mast cells in this process and to delineate the contractile prostanoid component of the hyperosmolar- induced response. It was established that hyperosmolar-induced prostanoid component consisted of PGD2 and thromboxane TXA2 released from mast cells, acting on the thromboxane receptor. It was also shown that the use of monensin, a drug that selectively kills mast cells, abolished the hyperosmolar-induced bronchoconstriction.

In Paper III, both isolated lung mast cells and human small bronchi were exposed to IL-33, TSLP and IL-25 and activated by hyperosmolar solution or IgE cross- linking (to mimic antigen). In the bronchi, the contractile responses and release of histamine and lipid mediators were assessed, and in the cells, degranulation and the release of histamine and lipid mediators were determined. It was discovered that IL-33, but not TSLP or IL-25, increased the contractile responses and the release of major prostanoids and histamine in response to both stimuli. The effect of IL-33 was then evaluated in the lung mast cells where it was found to increase degranulation, histamine release and release of cysteinyl leukotrienes, prostaglandins and several other lipid metabolites.

The findings presented in this thesis propose a specific role for IL-33 as enhancer of mast cell-dependent airway responses, supporting intervention with IL-33 as an attractive target for treatment of asthma and AHR. Furthermore, this thesis adds evidence that mast cells and their mediators have a crucial role in hyperosmolar induced bronchoconstriction.

List of scientific papers

I. Maria Belikova, Jesper Säfholm, Mamdoh Al-Ameri, Ann-Charlotte Orre, Sven-Erik Dahlén, Mikael Adner. Combined exposure to the alarmins TSLP, IL-33 and IL-25 enhances mast cell-dependent contractions of human bronchi. Clinical and Experimental Allergy. 2023, volume 53, issue 10, page 1062-1066.
https://doi.org/10.1111/cea.14367

II. Maria Belikova, Mamdoh Al-Ameri, Ann-Charlotte Orre, Jesper Säfholm. Defining the contractile prostanoid component in hyperosmolar-induced bronchoconstriction in human small airways. Prostaglandins and Other Lipid Mediators. 2023, volume 168, article 106761.
https://doi.org/10.1016/j.prostaglandins.2023.106761

III. Maria Belikova, Anna-Karin Johnsson, Johan Kolmert, Craig Wheelock, Willem Abma, Mamdoh Al-Ameri, Axel Dimberg, Erik Sachs, Kasra Vali Jalali, Mikael Adner, Gunnar Nilsson, Sven-Erik Dahlén, Jesper Säfholm. IL-33 enhances responsiveness and mast cell mediator release in isolated human airways. [Manuscript]