Continuous Inhalation Exposure to Fungal Allergen Particulates Induces Lung Inflammation While Reducing Innate Immune Molecule Expression in the Brainstem

Abstract

Continuous exposure to aerosolized fine (particle size ≤2.5 µm) and ultrafine (particle size ≤0.1 µm) particulates can trigger innate inflammatory responses in the lung and brain depending on particle composition. Most studies of manmade toxicants use inhalation exposure routes, whereas most studies of allergens use soluble solutions administered via intranasal or injection routes. Here, we tested whether continuous inhalation exposure to aerosolized Alternaria alternata particulates (a common fungal allergen associated with asthma) would induce innate inflammatory responses in the lung and brain. By designing a new environmental chamber able to control particle size distribution and mass concentration, we continuously exposed adult mice to aerosolized ultrafine Alternaria particulates for 96 hr. Despite induction of innate immune responses in the lung, induction of innate immune responses in whole brain samples was not detected by quantitative polymerase chain reaction or flow cytometry. However, exposure did trigger decreases in Arginase 1, inducible nitric oxide synthase, and tumor necrosis factor alpha mRNA in the brainstem samples containing the central nervous system respiratory circuit (the dorsal respiratory group, ventral respiratory group, and the pre-Bötzinger and Bötzinger complexes). In addition, a significant decrease in the percentage of Toll-like receptor 2-expressing brainstem microglia was detected by flow cytometry. Histologic analysis revealed a significant decrease in Iba1 but not glial fibrillary acidic protein immunoreactivity in both the brainstem and the hippocampus. Together these data indicate that inhalation exposure to a natural fungal allergen under conditions sufficient to induce lung inflammation surprisingly causes reductions in baseline expression of select innate immune molecules (similar to that observed during endotoxin tolerance) in the region of the central nervous system controlling respiration.

Novel Mechanical Strain Characterization of Ventilated ex vivo Porcine and Murine Lung using Digital Image Correlation

“…Such pulmonary imposed circumstances are presently escalated in the recent respiratory-borne COVID-19 pandemic causing over 460,000 deaths with over 8 million confirmed cases worldwide as of July 2020 (Almukhtar et al, 2020;World Health Organization, 2020). Lung pathologies, such as asthma, emphysema, and chronic obstructive pulmonary disease (COPD), often alter the structural properties of lung tissue, where smoking or air pollutants trigger inflammatory cell recruitment that subsequently induces fibrosis (Li et al, 1999;Eskandari et al, 2013;Peng et al, 2018) and leads to irreversible damage as the tissue remodels (James and Wenzel, 2007;Eskandari et al, , 2016. Induced lung dysfunction in asthma is associated with the loss of elasticity, airway narrowing, and obstruction in the lung (Gelb et al, 2002;; hamsters with induced emphysema experience a lower elastic recoil pressure (Niewoehner and Kleinerman, 1973); and COPD lungs exhibit both decreased lung distension and reduced anisotropic tissue behavior (Pan et al, 2020).…”

Interaction of Alt a 1 with SLC22A17 in the airway mucosa

“…A consequence of human exposure to fungal aeroallergens, sensitization to A. alternata, has been unequivocally associated with increased asthma severity and persistence. [10][11][12] In South Europe, over 20% of the patients with a history of respiratory allergy showed sensitization to Alternaria, 13 being Alt a 1 the most prevalent allergen. 6,7,14,15 Alt a 1 is a heat-stable, 30 kDa homodimer that dissociates into 14.5-and 16-kDa subunits under reducing conditions.…”

Aerosolized Desert Dusts Collected Near a Drying Lake and Pulmonary Inflammation in Mice: Implications for Environmental Exposures and Asthma

“…This is not a limitation of the relatively short term (7d) aerosol exposure, as similar exposure to aerosols of the fungal allergen Alternaria produces robust allergic inflammation within 4 to 7 days (Peng et al, 2018; Biddle et al, 2021). 21,35 Second, exposures of only 48 hours induced the strongest neutrophil recruitment (63.9 + 3.5% vs 0.1 + 0.03% in the airways; Fig2a; 41.2 + 10.4% vs 8.6 + 0.6% in the digested lung tissue; Fig.2c) with strong but slightly lower persistent inflammation present after 7 days of exposure (Fig.2a) and no recruitment of eosinophils at either timepoint (Fig.2b,d). Allergic stimuli such as Alternaria tend to have a stronger response at 7 days, as 48 hours does not appear to be enough to generate an adaptive response.…”