Abernathychase4623

Therefore, Nrf2 activator and NLRP3 inhibitor might be latent targets in the VILI prevention. BACKGROUND Allergens elicit host production of mediators acting on G-protein coupled receptors (GPCRs) to regulate airway tone. Among these is prostaglandin E2 (PGE2), which, in addition to its role as a bronchodilator, has anti-inflammatory actions. Some patients with asthma develop bronchospasm following ingestion of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), a disorder termed aspirin-exacerbated respiratory disease (AERD). This condition may result in part from abnormal dependence on the bronchoprotective actions of prostaglandin E2 (PGE2). OBJECTIVE We sought to understand the functions of Regulator of G Protein Signaling 4 (RGS4), a cytoplasmic protein expressed in airway smooth muscle (ASM) and bronchial epithelium that regulates activity of GPCRs, in asthma. METHODS We examined RGS4 expression in human lung biopsies by immunohistochemistry. We assessed airways hyper-responsiveness (AHR) and lung inflammation in germline and ASM-specific Rgs4-/- mice and in mice treated with an RGS4 antagonist following challenge with Aspergillus fumigatus. We examined the role of RGS4 in NSAID-associated bronchoconstriction by challenging AERD-like (ptges1-/-) mice with aspirin. RESULTS RGS4 expression in respiratory epithelium is increased in subjects with severe asthma. Allergen-induced AHR was unexpectedly diminished in Rgs4-/- mice, a finding associated with increased airway PGE2 levels. RGS4 modulated allergen-induced PGE2 secretion in human bronchial epithelial cells and prostanoid-dependent bronchodilation. The RGS4 antagonist CCG203769 attenuated AHR induced by allergen or aspirin challenge of wild type (WT) or ptges1-/- mice, respectively, in association with increased airway PGE2 levels. CONCLUSIONS RGS4 may contribute to the development of AHR by reducing airway PGE2 biosynthesis in allergen- and aspirin-induced asthma. BACKGROUND The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps (NPs), but upstream drivers of local antibody production in NPs are undetermined. OBJECTIVE We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells (AECs) in NPs from AERD subjects. METHODS Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis with NPs (CRSwNP), CRS without NPs (CRSsNP), and non-CRS controls. Tissue antibody levels were quantified via ELISA and immunohistochemistry, and were correlated with disease severity. AECs were profiled with single-cell RNA-sequencing (scRNA-seq), flow cytometry and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA-seq and qPCR. RESULTS Tissue IgE and IgG4 were elevated in AERD compared to controls (P less then 0.01 for IgE and P less then 0.001 for IgG4, vs. CRSwNP). AERD subjects whose NPs recurred rapidly had higher IgE levels than AERD subjects with slower regrowth (P=0.005). ScRNA-seq revealed increased IL5RA, IGHG4, and IGHE in AECs from AERD compared to CRSwNP. There were more IL-5Rα+ plasma cells in the polyp tissue from AERD than CRSwNP (P=0.026). IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts. CONCLUSIONS Our study identifies an increase in AECs in AERD defined by transcript enrichment of IL5RA and IGHG4 or IGHE, with confirmed surface expression of IL-5Rα, and functional IL-5 signaling. Tissue IgE and IgG4 are elevated in AERD and higher IgE levels are associated with faster NP regrowth. Our findings suggest a role for IL-5Rα+ AECs in facilitating local antibody production and severe NPs in AERD. BACKGROUND Scavenger receptor CD163 is exclusively expressed on monocytes/macrophages and is widely used as a marker for alternatively activated macrophages. However, the role of CD163 is not yet clear. OBJECTIVES We examined the function of CD163 in steady-state as well as in sterile and infectious inflammation. METHODS Expression of CD163 was analyzed under normal and inflammatory conditions in mice. Functional relevance of CD163 was investigated in models of inflammation in wildtype and CD163-/- mice. RESULTS We describe a subpopulation of BM resident macrophages (BMRM) which is characterized by a high expression of CD163 and is functionally distinct from classical bone marrow-derived macrophages (BMDM). Development of CD163+ BMRM is strictly dependent on interferon regulatory factor-8 (IRF8). CD163+ BMRM show a specific transcriptome and cytokine secretion pattern demonstrating a specific immunomodulatory profile of these cells. Accordingly, CD163-/- mice show a stronger inflammation in allergic contact dermatitis indicating a regulatory role of CD163. On the other hand, CD163-/- mice are highly susceptible to S. aureus infections demonstrating the relevance of CD163 for anti-microbial defense as well. CONCLUSION Our data indicate that anti-inflammatory and immunosuppressive mechanisms are not necessarily associated with a decreased antimicrobial activity. In contrast, our data define a novel macrophage population which controls overwhelming inflammation on one hand but is also necessary for an effective control of infections on the other hand. Currently, the Advisory Committee on Immunization Practices recommends one-time tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination for all adults 19 years and older. This study is designed to evaluate the cost-effectiveness of Tdap vaccination for Tdap-eligible adults aged 19 through 85 in the United States. A cost-effectiveness model was developed to compute costs and health outcomes associated with pertussis among 100,000 Tdap-eligible persons of each age cohort. selleck kinase inhibitor From the societal perspective, the cost per quality-adjusted life-year (QALY) saved was evaluated under the vaccination scenarios. Sensitivity analyses were also conducted to evaluate the impacts of changes in key variables. All costs were adjusted to 2018 US$ with an annual discount rate of 3% applied to costs and outcomes. The incremental cost-effectiveness ratios (ICERs) for vaccinating US adults aged 19 to 85 with Tdap ranged from $248,000/QALY to $900,000/QALY. The lowest cost per QALY was found to be $248,000 for the age 65 cohort, followed by $332,000 for the cohort of age 19, and followed by $477,000 for the age 50 cohort.