Granulocytic Airway Inflammation and Clinical Asthma Outcomes.
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ABSTRACT:
SUBMITTER: Louis RE
PROVIDER: S-EPMC8017566 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
Publications
Granulocytic Airway Inflammation and Clinical Asthma Outcomes.
Louis Renaud E RE Schleich Florence N FN
American journal of respiratory and critical care medicine 20210401 7
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Project description:Sensitization to fungi often leads to a severe form of asthma that is particularly difficult to manage clinically, resulting in increased morbidity and hospitalizations in these patients. Although B lymphocytes might exacerbate asthma symptoms through the production of IgE, these cells might also be important in the protective response against inhaled fungi. Through cytokine release and T-cell interactions, these lymphocytes might also influence the development and maintenance of airway wall fibrosis. J(H)(-/-) mice lack the JH gene for the heavy chain component of antibodies, which is critical for B-cell function and survival. These animals have facilitated the elucidation of the role of B lymphocytes in a number of immune responses; however, J(H)(-/-) mice have not been used to study fungal allergy. In this study, we examined the role of B lymphocytes using an Aspergillus fumigatus murine fungal aeroallergen model that mimics human airway disease that is triggered by environmental fungal exposure. We compared disease progression in sensitized wild-type BALB/c and J(H)(-/-) mice that were exposed to repeated fungal exposure and found no differences in airway hyperresponsiveness, overall pulmonary inflammation or collagen deposition around the large airways. However, the levels of the Th2-type cytokines IL-4 and IL-13 were significantly attenuated in the airways of J(H)(-/-) mice relative to the BALB/c controls. By contrast, levels of the inflammatory cytokines IL-17A and IL-6 were significantly elevated in the J(H)(-/-) animals, and there was significantly more robust airway eosinophilia and neutrophilia than in control animals. Taken together, these findings demonstrate that B lymphocytes help to regulate granulocytic responses to fungal exposure in the pulmonary compartment.
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Project description:Airway hyperresponsiveness (AHR) is a clinical feature of asthma and is often in proportion to the underlying severity of the disease. To understand AHR and the mechanisms that contribute to these processes, it is helpful to divide the airway components that affect this feature of asthma into "persistent" and "variable" categories. The persistent component of AHR represents structural changes in the airway, whereas the variable feature relates to inflammatory events. Insight into how these interrelated components of AHR can contribute to asthma is gained by studying treatment effects and models of asthma provocation.
| S-EPMC2914527 | biostudies-other
Project description:Severe asthma is characterized by steroid insensitivity and poor symptom control and is responsible for most asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding of mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in human asthmatic lungs. In this study, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and neutrophilic lung inflammation, pathology, airway remodeling, and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, retinoic acid-related orphan receptor γt (RORγt), and Th17 responses, with PRMT5-dependent increases in RORγt's agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.
| S-EPMC9055570 | biostudies-literature
Project description:BackgroundLess attention has been paid to the pathophysiological changes in atypical asthma such as cough variant asthma (CVA) and chest tightness variant asthma (CTVA). The obstruction of large and small airways is the important component in the development of asthma. We investigated whether small airway inflammation (SAI) induced small airway dysfunction (SAD) in these atypical asthmatics.MethodsSix hundred and eighty-six patients were enrolled and analyzed in the study. The partitioned airway inflammation was assessed by fractional exhaled nitric oxide (FeNO), such as FnNO, FeNO50, FeNO200, and calculated alveolar fraction of exhaled NO (CaNOdual). Correlations between exhaled NOs and SAD-related variables were assessed, whereas cell classification was evaluated by Spearman's rank tests. Classic asthma, CVA, and CTVA about potential risk were conducted using binary logistic regression models.ResultsThe whole airway inflammation increased in classic and atypical asthma than controls, whereas the central and peripheral airway inflammation in the CVA and CTVA groups increased compared with the classic asthma group. Smoking exposure was found to increase the central and peripheral airway inflammation in patients with asthma. The exhaled NO of FeNO50 and FeNO200 was associated with SAD in classic asthma, but not in CVA and CTVA. FeNO200 was the main risk (adjusted odds ratio [OR], 1.591; 95 % CI, 1.121-2.259; P = .009) in classic asthma and (adjusted OR, 1.456; 95 % CI, 1.247-1.700; P = .000) in CVA. The blood eosinophil levels were correlated with FeNO50 and FeNO200 in classic asthma and atypical asthma.ConclusionMore severe inflammatory process was present in central and peripheral airways in CVA and CTVA, which might reflect a pre-asthmatic state. SAI was the predominant risk factor in the development of asthma before SAD.
| S-EPMC11386289 | biostudies-literature
Project description:AimsTo examine whether asthma induced by exposure to aluminium potroom emissions (potroom asthma) is associated with inflammatory changes in the airways.MethodsBronchial biopsy specimens from 20 asthmatic workers (8 non-smokers and 12 smokers), 15 healthy workers (8 non-smokers and 7 smokers), and 10 non-exposed controls (all non-smokers) were analysed. Immunohistofluorescent staining was performed to identify mucosal total leucocytes (CD45+ leucocytes), neutrophils, and mast cells.ResultsMedian RBM thickness was significantly increased in both asthmatic workers (8.2 microm) and healthy workers (7.4 microm) compared to non-exposed controls (6.7 microm). Non-smoking asthmatic workers had significantly increased median density of lamina propria CD45+ leucocytes (1519 cells/mm2 v 660 and 887 cells/mm2) and eosinophils (27 cells/mm2 v 10 and 3 cells/mm2) and significantly increased concentrations of exhaled NO (18.1 ppb v 6.5 and 5.1 ppb) compared to non-smoking healthy workers and non-exposed controls. Leucocyte counts and exhaled NO concentrations varied with smoking habits and fewer leucocytes were observed in asthmatic smokers than in non-smokers Asthmatic smokers had significantly increased numbers of eosinophils in lamina propria compared to non-exposed controls (10 v 3 cells/mm2). Both eosinophilic and non-eosinophilic phenotypes of asthma were recognised in the potroom workers and signs of airway inflammation were also observed in healthy workers.ConclusionsAirway inflammation is a central feature of potroom asthma and exposure to potroom emissions induces pathological alterations similar to those described in other types of asthma. Cigarette smoking seems to affect the underlying mechanisms involved in asthma, as the cellular composition of airway mucosa appears different in asthmatic smokers and non-smokers.
| S-EPMC1763667 | biostudies-literature
Project description:IntroductionInnate immune activation through exposure to indoor and outdoor pollutants is emerging as an important determinant of asthma severity. For example, household levels of the bacterial product lipopolysaccharide (LPS) are associated with increased asthma severity. We hypothesized that activation of the innate immune receptor TLR5 by its bacterial ligand flagellin will exacerbate airway inflammation and asthma symptoms.MethodsWe determined the effect of flagellin co-exposure with ovalbumin in a murine model of allergic asthma. We evaluated the presence of flagellin activity in house dust of asthma patients. Finally, we analyzed the association of a dominant-negative polymorphism in TLR5 (rs5744168) with asthma symptoms in patients with asthma.ResultsWe showed that bacterial flagellin can be found in the house dust of patients with asthma and that this bacterial product exacerbates allergic airway inflammation in an allergen-specific mouse model of asthma. Furthermore, a dominant-negative genetic polymorphism in TLR5, the receptor for flagellin, is associated with decreased symptoms in patients with asthma.ConclusionTogether, our results reveal a novel genetic protective factor (TLR5 deficiency) and a novel environmental pollutant (microbial flagellin) that influence asthma severity. (Clinical trials NCT01688986 and NCT01087307).
| S-EPMC7123460 | biostudies-literature
Project description:Asthma is a chronic eosinophilic inflammatory disease with an increasing prevalence worldwide. Endocannabinoids are known to have immunomodulatory biological effects. However, the contribution of oleoylethanolamide (OEA) to airway inflammation remains to be elucidated. To investigate the effect of OEA, the expression of proinflammatory cytokines was measured by RT-qPCR and ELISA in airway epithelial (A549) cells. The numbers of airway inflammatory cells and cytokine levels in bronchoalveolar lavage fluid, airway hyperresponsiveness, and type 2 innate lymphoid cells (ILC2s) were examined in BALB/c mice after 4 days of OEA treatment. Furthermore, eosinophil activation after OEA treatment was evaluated by measuring cellular CD69 levels in eosinophils from human peripheral eosinophils using flow cytometry. OEA induced type 2 inflammatory responses in vitro and in vivo. OEA increased the levels of proinflammatory cytokines, such as IL-6, IL-8, and IL-33, in A549 cells. In addition, it also induced eosinophilic inflammation, the production of IL-4, IL-5, IL-13, and IL-33 in bronchoalveolar lavage fluid, and airway hyperresponsiveness. OEA increased the numbers of IL-5- or IL-13-producing ILC2s in a mouse model. Finally, we confirmed that OEA increased CD69 expression (an eosinophil activation marker) on purified eosinophils from patients with asthma compared to those from healthy controls. OEA may play a role in the pathogenesis of asthma by activating ILC2s and eosinophils.
| S-EPMC8257664 | biostudies-literature
Project description:BackgroundPentraxin 3 (PTX3) regulates multiple aspects of innate immunity and tissue inflammation. Recently, it has been reported that PTX3 deficiency enhances interleukin (IL)-17A-dominant pulmonary inflammation in an ovalbumin (OVA)-induced mouse asthma model. However, whether PTX3 treatment would provide protection against allergic airway inflammation has not been clearly elucidated. The goal of this study was to further investigate the effect of recombinant PTX3 administration on the phenotype of asthma.MethodsC57BL/6 J mice were sensitized and challenged with OVA to induce eosinophilic asthma model, as well as sensitized with OVA plus LPS and challenged with OVA to induce neutrophilic asthma model. We evaluated effect of recombinant PTX3 on asthma phenotype through both asthma models. The bronchoalveolar lavage fluid (BALF) inflammatory cells and cytokines, airway hyperresponsiveness, and pathological alterations of the lung tissues were assessed.ResultsIn both eosinophilic and neutrophilic asthma models, PTX3 treatment provoked airway hyperresponsiveness, concomitant with increased inflammatory cytokines IL-4, IL-17, eotaxin, and transforming growth factor (TGF)-β1 and aggravated airway accumulation of inflammatory cells, especially eosinophils and neutrophils. In histological analysis of the lung tissue, administration of PTX3 promoted inflammatory cells infiltration, mucus production, and collagen deposition. In addition, PTX3 also significantly enhanced STAT3 phosphorylation in lung tissue.ConclusionOur results show that exogenous PTX3 can exacerbate multiple asthmatic features by promoting both eosinophils and neutrophils lung infiltration and provide new evidence to better understand the complex role of PTX3 in allergic airway inflammation.
| S-EPMC7493172 | biostudies-literature
Project description:The unfolded protein response (UPR) is associated with the risk of asthma, including treatment-refractory severe asthma. Recent studies demonstrated a pathogenic role of activating transcription factor 6a (ATF6a or ATF6), an essential UPR sensor, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by signal transducer and activator of transcription6 (STAT6) and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specific Atf6-deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed the expression of ATF6 downstream genes and TH cell cytokines by both murine and human memory clusters of differentiation 4 (CD4)+ T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responses, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.
| S-EPMC10530451 | biostudies-literature
Project description:BackgroundAsthma is a heterogenous disease that can be classified into eosinophilic (type 2-high) and noneosinophilic (type 2-low) endotypes. The type 2-low endotype of asthma can be characterized by the presence of neutrophilic airway inflammation that is poorly responsive to corticosteroids. Dysregulated innate immune responses to microbial products including Toll-like receptor (TLR) ligands have been associated with the pathogenesis of neutrophilic asthma. The key molecules that regulate inflammatory responses in individuals with neutrophilic asthma remain unclear. We previously reported that the immunoregulatory receptor neuropilin-2 (NRP2) is expressed by murine and human alveolar macrophage (AM) and suppresses lipopolysaccharide (LPS)-induced neutrophilic airway inflammation.MethodsHere, we investigated the immunoregulatory role of NRP2 in a mouse model of neutrophilic asthma.ResultsWe found that TLR ligands, but not T helper 2 (Th2)-promoting adjuvants, induced NRP2 expression by AM. Using an LPS-mediated model of neutrophilic asthma, we demonstrate that NRP2 was increased in AM and other lung antigen-presenting cells following airway challenge with antigen. Conditional deletion of NRP2 in myeloid cells exacerbated airway inflammation in a neutrophilic asthma model. In contrast, myeloid-specific ablation of NRP2 did not affect airway inflammation in a Th2-mediated eosinophilic asthma model. Myeloid-specific ablation of NRP2 did not affect Th1/Th17 responses to inhaled antigens or expression of neutrophil chemokines but rather resulted in impaired efferocytosis by AM, which is necessary for effective resolution of airway inflammation.ConclusionOur findings suggest that NRP2 is a negative regulator of airway inflammation associated with neutrophilic asthma.
| S-EPMC8926497 | biostudies-literature