Inflammatory mechanisms linking maternal and childhood asthma

Abstract

Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Asthma often develops during childhood and causes lifelong decrements in lung function and quality of life. Risk factors for childhood asthma are numerous and include genetic, epigenetic, developmental, and environmental factors. Uncontrolled maternal asthma during pregnancy exposes the developing fetus to inflammatory insults, which further increase the risk of childhood asthma independent of genetic predisposition. This review focuses on the role of maternal asthma in the development of asthma in offspring. We will present maternal asthma as a targetable and modifiable risk factor for childhood asthma and discuss the mechanisms by which maternal inflammation increases childhood asthma risk. Topics include how exposure to maternal asthma in utero shapes structural lung development with a special emphasis on airway nerves, how maternal type-2 cytokines such as IL-5 activate the fetal immune system, and how changes in lung and immune cell development inform responses to aero-allergens later in life. Finally, we highlight emerging evidence that maternal asthma establishes a unique "asthma signature" in the airways of children, leading to novel mechanisms of airway hyperreactivity and inflammatory cell responses.

Keywords: asthma; childhood; developmental origins; eosinophil; inflammation; maternal; nerves.

FIGURE 1. Mechanisms of increased childhood asthma risk in offspring born to mothers with asthma.

(A) Under homeostatic conditions, afferent sensory nerves detect external stimuli and activate efferent parasympathetic nerves through a central nerve-reflex pathway. Parasympathetic nerves release acetylcholine (ACh) onto airway smooth muscle M3-muscarinic receptors (M3) to induce airway contraction. M2-muscarinic receptors (M2) located on presynaptic postganglionic nerves inhibit further acetylcholine release. (B) Maternal asthma increases airway hyperreactivity and bronchoconstriction in offspring by inducing airway sensory hyperinnervation, basement membrane thickening, and smooth muscle hypertrophy. In mice, developmental reprogramming is mediated by maternal IL-5 and fetal eosinophils. Eosinophils also increase bronchoconstriction by releasing cationic proteins that inhibit M2-muscarinic receptor function and potentiate acetylcholine release