Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

Abstract

After a single or multiple intratracheal instillations of Stachybotrys chartarum (S. chartarum or black mold) spores in BALB/c mice, we characterized cytokine production, metabolites, and inflammatory patterns by analyzing mouse bronchoalveolar lavage (BAL), lung tissue, and plasma. We found marked differences in BAL cell counts, especially large increases in lymphocytes and eosinophils in multipledosed mice. Formation of eosinophil-rich granulomas and airway goblet cell metaplasia were prevalent in the lungs of multiple-dosed mice but not in single-or saline-dosed groups. We detected changes in the cytokine expression profiles in both the BAL and plasma. Multiple pulmonary exposures to S. chartarum induced significant metabolic changes in the lungs but not in the plasma. These changes suggest a shift from type 1 inflammation after an acute exposure to type 2 inflammation after multiple exposures to S. chartarum. Eotaxin, vascular endothelial growth factor (VEGF), MIP-1a, MIP-1b, TNF-a, and the IL-8 analogs macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemoattractant (KC), had more dramatic changes in multiplethan in single-dosed mice, and parallel the cytokines that characterize humans with histories of mold exposures versus unexposed control subjects. This repeated exposure model allows us to more realistically characterize responses to mold, such as cytokine, metabolic, and cellular changes.

Inhalation of Stachybotrys chartarum Fragments Induces Pulmonary Arterial Remodeling

“…Previous data from our laboratory and others demonstrate pulmonary pathology after S. chartarum exposure (24,25,30,31); however, the underlying mechanisms need further clarification. The aim of this study was to characterize the mechanisms contributing to the pulmonary immune responses after repeated exposure to S. chartarum.…”

“…The present study used two different S. chartarum strains that included a high-fragmenting isolate and a low-fragmenting isolate. Aerosolized S. chartarum was repeatedly delivered to mice housed in a nose-only chamber to more closely mimic natural human exposure, a documented methodological advancement over studies using intranasal instillations, intratracheal instillations, or liquid aerosol inhalations (20)(21)(22)(23)(24)(25)(26). This model has been validated by characterizing the immune response and genetic profile after Aspergillus fumigatus exposure (27)(28)(29).…”

A Novel Link between Early Life Allergen Exposure and Neuroimmune Development in Children

“…These changes suggest a shift from type 1 inflammation after an acute exposure to type 2 inflammation after multiple exposures to S. chartarum. Eotaxin, vascular endothelial growth factor (VEGF), MIP-1α, MIP-1β, TNF-α, and the IL-8 analogs macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemoattractant (KC), had more dramatic changes in multiple-than in single-dosed mice, and parallel the cytokines that characterize humans with histories of mold exposures versus unexposed control subjects [21].…”

Killing Two Birds with One Stone: Mold-induced Pulmonary Immune Responses and Arterial Remodeling

“…Responses to mold are influenced by the genetics of both mold and mice. Rosenblum Lichtenstein and colleagues (9)(10)(11) showed that different strains of mice respond differently to mold. Croston and colleagues show that repeated exposures to two different strains of S. chartarum lead to different patterns of inflammation and arterial remodeling (1).…”

“…Mold antigens and macrocyclic trichothecenes may elicit immune responses after repeated exposures (10,11). Importantly, the Croston paper describes repeatedly exposed mice.…”