Asthma due to exposure to allergens and other environmental pollutants: inflammatory and immunologic response

Abstract

Air pollution has emerged as a critical global health issue, significantly contributing to the development and exacerbation of respiratory diseases. Among the sources of air pollution, road traffic constitutes the main cause in urban areas. Traffic-related emissions are conformed mainly by diesel exhaust particles (DEPs), which have been recognized by the World Health Organization (WHO) as one of the most harmful components of air pollution, as they penetrate the lungs producing a carcinogenic effect and disrupting immune and respiratory function. Concretely, DEPs induce oxidative stress, inflammation, and immune dysregulation. While studies have explored the effects of pollution on respiratory diseases such as asthma, particularly in vulnerable populations like children and the elderly, the specific immunological pathways-especially in healthy individuals-remain poorly understood. This PhD thesis aims to identify the mechanisms by which air pollution exposure induces harmful effects in individuals with chronic respiratory diseases, specifically asthma, and to compare these mechanisms with those affecting healthy individuals. Article 1 determined the immunomodulatory potential of DEPs after a short-, mid- and long-time exposure in a murine model of healthy mice. It was determined DEPs induced a two-phase immune response in our healthy mice. The first phase, equivalent to short DEPs exposure, is characterized by a decrease in lung functional parameters due to an inflammatory state mediated by neutrophilic and eosinophilic responses, affecting primarily the small airways. During this short exposure alveolar macrophages (AM) phagocytose DEPs to clear both lumen and tissue. However, with high DEPs accumulation AM may undergo depletion leading to neutrophilic recruitment, but also inducing a differentiation of inflammatory monocytes into interstitial macrophages (IM), which could culminate in a switch of the macrophage subpopulation and make the tissue a pro-inflammatory microenvironment. In the second phase, healthy mice recover the lung function parameters with values similar to those in non-exposed mice, and there is no more eosinophilia- neutrophilia-mediated inflammation. The remaining tissue resident macrophages undergo an exhaustion process which may culminate in the loss of their phagocytic capacity. In response, dendritic cells (DCs) replace macrophages in regulating the immune response, acting as key intermediators in the change from an innate to an adaptive response. All these data suggest that continuous DEPs exposure triggers immune mechanisms that predispose healthy individuals to a pro-inflammatory and hyper-reactive microenvironment. Article 2 presents the results of a prospective, observational in real-life study performed in asthmatic patients and a healthy control group after a short-term exposure (2-hour) to two environments, a polluted vs a non-polluted environment, determining the lung function, oxidative stress, inflammatory and immune biomarkers. This article deeps on the different mechanisms by which environmental pollution can deteriorate the respiratory health of not only asthmatic patients, but also healthy people after a short exposure to air pollution. Prolonged exposure to pollutants leads to persistent oxidative stress and systemic inflammation, which have been linked to the progression of respiratory diseases, accelerated lung function decline, and increased asthma risk. No differences in the lung function were stablished. However, significant immune alterations were determined during this article. In healthy individuals, there is an adaptive suppression of immune activity to mitigate the excessive inflammation triggered by pollutants with the increase of chemoattract (CXCL8 and CCL2) and regulatory cytokines (IL7) and a reduction of tissue remodeling cytokines (OSM and HGF). Conversely, asthmatics present a more marked inflammatory response, primarily mediated by IL1β and IL15, probably due to the pre-existing chronic inflammation. Both groups presented a common mechanism by the increase of CSF2 and IL17F leading to the activation of macrophages, neutrophils and Th17 cells

Date of Award	19 Sept 2025
Original language	English
Supervisor	Xavier Muñoz Gall (Director) & Maria Jesus Cruz Carmona (Director)