Mechanisms of perinatal nicotine vaping-induced pulmonary ILC2 dysregulation and allergic asthma development

The National Heart Lung and Blood Institute awarded $827,439 to Lundquist Institute For Biomedical Innovation At Harbor-UCLA Medical Center on September 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate mechanisms by which perinatal nicotine vaping exposure dysregulates pulmonary group 2 innate lymphoid cells (ILC2s) and promotes allergic asthma development in offspring.

The research employs electronic nicotine delivery system (ENDS) exposure models and innovative molecular tools including NMUR1CRERORAFLX and nicotinic acetylcholine receptor A7 (NACHRA7) knockout mouse models, single-cell RNA sequencing, ATAC sequencing, and t-distributed stochastic neighbor embedding cytometric analyses. Aim 1 examines whether perinatal nicotine vaping produces allergic airway hyper-responsiveness and the centrality of ILC2s in this response. Aim 2 focuses on molecular mechanisms, particularly the role of NACHRA7 on ILC2s subpopulations, transcriptomic and epigenomic changes, and effector functions. Aim 3 evaluates whether short-chain fatty acid butyrate supplementation, a clinically translatable therapeutic, mitigates perinatal nicotine vaping-induced ILC2 dysfunction, metabolic consequences of gut dysbiosis, and offspring airway hyper-responsiveness. Preliminary data show that perinatal nicotine exposure via both parenteral and inhaled routes increases lung ILC2 numbers and enhances allergic responses.

Performance occurs in Torrance, California. The period of performance extends from September 1, 2026, through May 31, 2030. The award is a Project Grant, an assistance type supporting investigator-initiated research.

Abstract

Asthma is a major public health issue, with 28 million individuals affected in the U.S., including a significant pediatric burden. Exposure to perinatal nicotine, through cigarette smoke or vaping, is a critical contributor to asthma pathogenesis and other allergic diseases, with evidence of lifelong and transgenerational impacts. Pulmonary group 2 innate lymphoid cells (ILC2S) are pivotal in allergic airway hyper-responsiveness (AHR) in adults, yet their role in perinatal nicotine smoking/vaping exposure-induced asthma remains unexplored. This proposal investigates how exposure to perinatal nicotine vaping modulates ILC2S and their interactions with the maternal and offspring metabolic milieu, focusing on TH2 polarization and allergic AHR. Using a well-established electronic nicotine delivery system (ENDS) and innovative tools, including the NMUR1CRERORAFLX and nicotinic acetylcholine receptor Α7 (NACHRΑ7) KO mouse models, single-cell RNA sequencing, atac sequencing, and T-distributed stochastic neighbor embedding (T-SNE) cytometric analyses, we aim to elucidate mechanisms driving nicotine-induced ILC2 activation. Aim 1 examines whether perinatal nicotine vaping results in allergic AHR and the centrality of ILC2 in this response, assessing how nicotine exposure impacts ILC2S in the lung. Aim 2 focuses on determining the molecular mechanisms, particularly the role of NACHRΑ7 on ILC2S subpopulations, transcriptomic and epigenomic changes, and effector functions. Aim 3 evaluates whether short chain fatty acid (SCFA) butyrate supplementation, a clinically translatable therapeutic, mitigates perinatal nicotine vaping exposure-induced ILC2 dysfunction, metabolic consequences of GUT dysbiosis, and offspring AHR. Our preliminary data show that perinatal nicotine exposure via both parenteral and inhaled routes increases lung ILC2 numbers and enhances TH2 cytokine secretion in response to IL-33 and house dust mite stimulations. Maternal nicotine exposure also alters GUT microbiota and reduces scfas, key modulators of ILC2 activity. Notably, butyrate supplementation significantly reduces TH2 cytokine production and cytokines mediating AHR in mouse models, highlighting its therapeutic potential. This study bridges critical gaps in understanding perinatal nicotine-induced ILC2 dysregulation, linking maternal metabolic alterations to offspring asthma. By identifying novel clinically easily translatable therapeutic strategies, our findings will inform interventions to mitigate perinatal nicotine exposure-related asthma and address this growing public health crisis.