Efectes de les partícules dièsel sobre l'asma al·lèrgic i induït per químics
- Autores: Miquel de Homdedeu Cortés
- Directores de la Tesis: M. Jesús Cruz Carmona (dir. tes.), Xavier Muñoz (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
- Idioma: catalán
- Tribunal Calificador de la Tesis: Vicente Plaza Moral (presid.), Ramon Orriols Martínez (secret.), Joan Bartra Tomás (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Air pollution is known to induce and exacerbate asthma pathophysiology, but the immunological effects of diesel exhaust particles (DEP) are still not well characterized and seem to differ depending on the pre-existing asthma endotype: type 2 (T2), which is subdivided further into Th2 and ILC2-driven; non-T2; and a mixed Th2/Th17 endotype. In the T2 endotype, traffic-related air pollution (TRAP) has been demonstrated to enhance respiratory sensitization to environmental allergens, while it has been suggested that DEPs act as adjuvants in the induction of allergic asthma. In the Th2-driven T2 endotype it seems that DEPs may increase the antigenic capacity of certain aeroallergens; while in the ILC2-driven T2 endotype, they may stimulate lung epithelial cells to produce high levels of interleukin (IL)-33, IL-25, and thymic stromal lymphopoietin (TSLP), cytokines related to ILC2s and eosinophilic asthma. In the non-T2 endotype, DEPs may aggravate neutrophilic asthma by increasing the production of both IL-17A and IL-17F cytokines. Lastly, our group reported that coexposure to soybean hull extract (SHE) and DEPs may favour a mixed Th17/Th2 response, not only involving a Th2 inflammation with IL-4, IL-5, IL-13 and IL-10, but also increasing levels of chemokines related to the Th17 response such as IL-17A, IL-17F, and CCL20 cytokines.
The present doctoral thesis aims to study the effects of DEP exposure on two different asthma endotypes by assessing respiratory mechanics, airway hyperresponsiveness (AHR), innate and adaptive immune responses, oxidative stress and particle deposition patterns. The first study (Chapter 1) aims to study the effects of DEP exposure in a mouse model of chemical-induced asthma due to ammonium persulfate (AP), a non-type 2 endotype. This study demonstrates that sensitization and inhalation of AP induce a T2 low asthma endotype, characterized by asthma-like lung parameters such as higher levels of central airway resistance, tissue elastance, and AHR, and airway inflammation consisting in eosinophilia, and lower levels of tolerogenic dendritic cells (DC). The DEP-exposed group showed slightly modified lung mechanics, airway inflammation with neutrophilia, higher levels of Th2-related DCs, lower levels of alveolar macrophages, and reduced levels of cytokines such as IL-13 and IFN-γ. The group coexposed to AP and DEPs presented exacerbated signs of asthma consisting principally of asthma-like lung function, airway inflammation with higher levels of oxidative stress-sensitive DCs, lower total macrophages, and a differential pattern of DEPs deposition in the lungs, restricted to large conducting airways.
The second study (Chapter 2) aims to study the effects of DEPs exposure in a mouse model exposed to non-asthmagenic doses of SHE, a Type 2 endotype. In this second chapter, the inhalation of 3 mg·ml-1 SHE induced a mild airway inflammation consisting in increased levels of eosinophils, B cells, Th2-related DCs, total and resident monocytes, and reductions in levels of NK cells, tolerogenic DCs, total and alveolar macrophages. The inhalation of DEPs alone triggers airway inflammation with neutrophilia. Lastly, the inhalation of SHE and DEPs together induced a mixed Th2/Th17 asthma endotype characterized by asthma-like lung function with higher levels of AHR and central airway resistance (Rn), airway inflammation consisting in higher levels of SHE-specific immunoglobulin (Ig)-E in serum, H2O2 in bronchoalveolar lavage (BAL), NK cells, oxidative stress-sensitive DCs, and lower levels of Th1-related DCs.
