PAI-1, Early Life Infections and Asthma Risk, Exacerbations, and Reduced Lung Function

Abstract

RATIONALE: Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines (IL-5 and IL-13), facilitate eosinophilic inflammatory responses in murine asthma models in the absence of CD4+ T lymphocytes. Localized activation of ILC2 is associated with uncontrolled airway eosinophilia in prednisone-dependent severe asthmatics. This study investigated the role of ILC2 in the development of eosinophilia in allergic asthma. METHODS: In a diluent-controlled allergen (Ag)-challenge cross-over study, ILC2s (lin-FcεRI-CD45+CD127+ST2+CRTH2+), CD4+ T lymphocytes, and levels of intracellular IL-5 and IL-13 expression were enumerated by flow cytometry in steroid-naive mild atopic asthmatics. All subjects (n57) developed Ag-induced dual bronchoconstriction, airway eosinophilia and increased methacholine airway responsiveness. Bone marrow, blood and sputum samples were collected pre-, 24 and 48h postchallenge and immediately fixed in 1% paraformaldehyde prior to immunofluorescence staining. RESULTS: Compared to pre-Ag levels, there was a significant increase in sputum ILC2 at 24h (P<0.01) which decreased to baseline levels 48h post-Ag. This was co-incident with a significant decrease in blood and bone marrow ILC2 at 24h post-Ag compared to pre-Ag levels. Activated ILC2 (IL5+ or IL13+) in sputum increased significantly at 24 h post-Ag only. In contrast, although total CD4+ T lymphocytes and IL-13+CD4+ T cells increased at 24h post-Ag (P<0.01), IL-5+CD4+ T cells only showed a trend for an increase at 48h post-Ag. No effect of diluent was observed. CONCLUSIONS: Our findings suggest that post-allergen exposure in mild atopic asthmatics, ILC2 may initiate the development of eosinophilic inflammation while CD4+ T lymphocytes may be involved in the persistence of the asthmatic response.

Bacterial Proteases as Potentially Exploitable Modulators of SARS-CoV-2 Infection: Logic from the Literature, Informatics, and Inspiration from the Dog

“…Patient abundance of SERPINA3/A1AC, by contrast, is proposed to be very important for COVID-19 outcomes, but the relationship is directly analogous to trends for asthmatics, such that A1AC deficiency could be considered a major risk factor for both allergic asthma and severe viral infections [145][146][147]. Finally, as a converse example, SERPINE1/PAI-1 overabundance seems to correlate strongly with both severe non-infectious respiratory pathology [141,[148][149][150] and a propensity to foster coagulopathic outcomes in severe COVID-19 cases, including interrelated acute respiratory distress syndrome (ARDS) and thrombotic manifestations [151][152][153], through apparent impairment of fibrinolytic activity [151]. From this complexity, it may be reasonable to conclude that some SERPINs have significant effects on both infectious and autoimmune respiratory pathologies, but that the effects are independent of any net relationship between cases of allergic asthma and trends of diminished COVID-19 severity.…”