How Type 2 Cytokines Burden Severe Asthma


There’s a challenge to achieve control in some asthma patients since the disease is heterogenous—both allergic and non-allergic triggers can initiate Type 2 inflammatory pathways that can drive pathology.

Nicola Hanania, MD, MS

Nicola Hanania, MD, MS

Characterized by continuing exacerbations, severe asthma lays a heavy burden on patients by decreasing their quality of life and ability to breathe easily. To investigate some of the driving factors behind this burdensome disease, Nicola Hanania, MD, MS, Baylor College of Medicine, looked at the Type 2 cytokines in its airway pathology.

Among his findings presented at the 2018 CHEST Annual Meeting in San Antonio, TX, ongoing consequences associated with continuing exacerbations, oral corticosteroid (OCS) use, and poor disease control were found, along with a drive to understand the heterogeneity and complexities of the pathobiology of Type 2 inflammation. IL-13 and the levels of mucus plugging also stood out as primary components to consider.

After first highlighting the goals of asthma management, which include having current control and preventing future risks through a cycle of assessments, treatment adjustments, and response reviews, Hanania moved into studies.

As poor asthma control can lead to increased exacerbations and expensive healthcare that can include hospitalizations, the vicious cycle of continuing exacerbations stood as the most important influence of clinical decision-making among those at the presentation, according to a virtual quiz.

However, Hanania explained that it can be challenging to achieve control in some asthma patients since the disease is heterogenous in nature. Consequently, both allergic and non-allergic triggers can initiate Type 2 inflammatory pathways that can drive pathology in asthma. Specifically, Hanania discussed the overlap between allergic eosinophilic asthma phenotypes in Type 2 high asthma.

Some unique and overlapping roles for Type 2 Cytokines included focuses on IL-4, IL-13, IL-5.

TH2 cell differentiation included IL-4; Goblet cell hyperplasia, mucus production, collagen deposition, and airway smooth muscle hypertrophy included IL-13; B cell isotype switching and IgE production included IL-4 and IL-13; eosinophil chemotaxis (recruitment) to inflamed lung tissue and promotion of tissue eosinophilia included IL-4, IL-13, and IL-5; and eosinophil differentiation in the bone marrow and survival in circulation included IL-5.

According to another virtual poll in the session, the differentiation of TH2 cells concerning the function of IL-4 were considered a unique function of IL-4.

Beyond inflammation, Hanania also covered the pathological effects of Type 2 cytokines on airway epithelium and smooth muscle as airway epithelial remodeling effects have been shown in patients with moderate to severe asthma. Specifically, thicker airway epithelium, lamina reticularis, and goblet cell hyperplasia are often evident in moderate and severe asthma.

Additionally, Hanania showed that mucus plugging and the degree of airflow obstruction are associated with increased markers for type 2 inflammation. Increased levels of mucus plugging are also associated with reduced lung function (FEV1, FVC, FEV1/FVC), sputum and blood eosinophilia, and elevated FeNO (high mucus scores only).

Mucus plugging also associated with increased MUC5AC sputum gene expression in patients with asthma.

Furthermore, IL-13-mediated effects on mucin expression in airway epithelial cells is consistent with the pre-steroid increase in the MUC5AC:MUC5B ratio. Mucostasis is caused by the tethering of MUC5AC-containing domains to epithelium; Hanania pointed this function also likely represents a major cause of mucus plugging in asthma.

The overexpression of IL-13 in mice has also shown to lead to mucous call hyperplasia and mucus production.

In vitro experiments also demonstrate IL-13’s potential roles in airway fibrosis, which may include an induced secretion of pro-fibrotic growth factors and proliferation of airway fibroblasts from patients with asthma as well as stimulation of the human lung fibroblast invasiveness.

Regarding airway smooth muscle, IL-13 may also contribute to airway hyperresponsiveness (AHR), increasing airway smooth muscle contractility as a result. In mice, IL-13 caused rapid AHR. Hanania noted that AHR response occurs independently of IL-5 and eotaxin, which suggests an IL-13-induced effect.

Additionally, IL-4 and IL-13 have been found to synergize with FGF2 to increase human bronchial smooth muscle cell proliferation in vitro.

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