Different Phenotypes in Asthma: Clinical Findings and Experimental Animal Models

Lourenço, Luiz Otávio; Ribeiro, Alessandra Mussi; Lopes, Fernanda Degobbi Tenório Quirino dos Santos; Tibério, Iolanda de Fátima Lopes Calvo; Tavares-de-Lima, Wothan; Prado, Carla M.

doi:10.1007/s12016-021-08894-x

Cited by 14 publications

(5 citation statements)

References 205 publications

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“…The heterogeneity of asthma airway inflammation or differences in asthma phenotypes could account for the disparities in TIPE2 levels in asthma patients. Significantly dissimilar infiltration of inflammatory cells and cytokines has been observed in different inflammatory phenotypes of asthma ( 34 – 36 ). TIPE2 in sputum of asthma patients positively correlated with pro-eosinophilic inflammation cytokines but negatively correlated with pro-neutrophilic inflammation cytokines.…”

Section: Discussionmentioning

confidence: 99%

TIPE2 May Target the Nrf2/HO-1 Pathway to Inhibit M1 Macrophage–Related Neutrophilic Inflammation in Asthma

Shi

Hao

et al. 2022

Front. Immunol.

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PurposeAlthough recent studies have highlighted the link of TIPE2 and asthma airway inflammation, its roles and molecular mechanisms in different asthma inflammatory phenotypes remain largely unknown. We evaluated sputum TIPE2 expression level and its correlation with different asthma phenotypes. Additionally, we explored the roles and mechanism of TIPE2 in M1 polarization of macrophages.MethodsA total of 102 asthma patients who underwent sputum induction were enrolled to evaluate the expression level of TIPE2 and its association with different asthma phenotypes. To explore the roles and mechanism of TIPE2 in M1 polarization of macrophages, THP-1 monocytes stimulated with phorbol-12-myristate-13-acetate, were used as a model of undifferentiated (M0) macrophages, and M0 macrophages were treated with lipopolysaccharide to induce M1 macrophages.ResultsThe sputum TIPE2 level was significantly lower in patients with neutrophilic asthma (NA) and higher in patients with eosinophilic asthma (EA) compared with patients with paucigranulocytic asthma. The levels of IL-1β, TNF-α and IL-6 were highest in NA compared with other groups. TIPE2 levels in sputum negatively correlated with IL-1β and TNF-α levels but positively correlated with IL-4, IL-5, IL-13, and IL-10 levels (P < 0.05). In vitro, TIPE2 enhanced Nrf2/HO-1 pathway activation in macrophages and inhibited LPS-induced M1 macrophage differentiation and related cytokine release. Further analysis showed that the Nrf2 inhibitor ML385 weakened TIPE2-induced activation of the Nrf2/HO-1 pathway, as well as TIPE2-induced suppression in M1 polarization of macrophage and inflammatory cytokines secretion.ConclusionsTIPE2 expression level was highly down-regulated in NA and was negatively correlated with inflammatory factors (IL-1β and TNF-α). Aberrant expression of TIPE2 may target the Nrf2/HO-1 pathway to inhibit M1 macrophage–related neutrophilic inflammation in asthma.

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Section: Discussionmentioning

confidence: 99%

TIPE2 May Target the Nrf2/HO-1 Pathway to Inhibit M1 Macrophage–Related Neutrophilic Inflammation in Asthma

Shi

Hao

et al. 2022

Front. Immunol.

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“…Allergic disorders, in particular BA, are multifactorial diseases in which genetic and environmental factors interact with each other [ 20 , 21 ]. BA displays a marked heterogeneity regarding etiology, symptom triggers and onset, clinical features, and response to therapy [ 22 , 23 , 24 , 25 ]. Indeed, the term asthma refers to a generic diagnosis including several clinical conditions (phenotypes) associated with distinctive functional or pathophysiologic mechanisms (endotypes) [ 26 , 27 ].…”

Section: Pathogenetic Mechanisms Of Allergic Responsementioning

confidence: 99%

How the Immune System Responds to Allergy Immunotherapy

et al. 2022

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IgE-mediated diseases represent a highly diversified and multifactorial group of disorders that can deeply impact the patients’ quality of life. Currently, allergy immunotherapy (AIT) still remains the gold standard for the management of such pathologies. In this review, we comprehensively examine and discuss how AIT can affect both the innate and the adaptive immune responses at different cell levels and propose timing-scheduled alterations induced by AIT by hypothesizing five sequential phases: after the desensitization of effector non-lymphoid cells and a transient increase of IgE (phase 1), high doses of allergen given by AIT stimulate the shift from type 2/type 3 towards type 1 response (phase 2), which is progressively potentiated by the increase of IFN-γ that promotes the chronic activation of APCs, progressively leading to the hyperexpression of Notch1L (Delta4) and the secretion of IL-12 and IL-27, which are essential to activate IL-10 gene in Th1 and ILC1 cells. As consequence, an expansion of circulating memory Th1/Tr1 cells and ILC-reg characterizes the third phase addressed to antagonize/balance the excess of type 1 response (phase 3). The progressive increase of IL-10 triggers a number of regulatory circuits sustained by innate and adaptive immune cells and favoring T-cell tolerance (phase 4), which may also be maintained for a long period after AIT interruption (phase 5). Different administration approaches of AIT have shown a similar tailoring of the immune responses and can be monitored by timely, optimized biomarkers. The clinical failure of this treatment can occur, and many genetic/epigenetic polymorphisms/mutations involving several immunological mechanisms, such as the plasticity of immune responses and the induction/maintenance of regulatory circuits, have been described. The knowledge of how AIT can shape the immune system and its responses is a key tool to develop novel AIT strategies including the engineering of allergen or their epitopes. We now have the potential to understand the precise causes of AIT failure and to establish the best biomarkers of AIT efficacy in each phase of the treatment.

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“…BALB/c mice are currently the most commonly used model to investigate asthma mechanisms. This strain of mouse can provide exuberant and appropriate AHR and Th2 responses that are notable in asthma 4 . However, mice do not spontaneously develop asthma, 5 and experimental strategies must be employed to induce the asthmatic‐like reaction to investigate the physiopathology of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…This strain of mouse can provide exuberant and appropriate AHR and Th2 responses that are notable in asthma. 4 However, mice do not spontaneously develop asthma, 5 and experimental strategies must be employed to induce the asthmatic‐like reaction to investigate the physiopathology of the disease. Mouse models for allergic asthma have been developed using various environmental risk factors, such as chicken egg ovalbumin (OVA), house dust mite, cockroach, and birch pollen.…”

Section: Introductionmentioning

confidence: 99%

Effects of increasing sensitizing doses of ovalbumin on airway hyperresponsiveness in asthmatic mice

Chen,

Yuan,

Peng

et al. 2024

Immunity Inflam & Disease

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BackgroundThe dosage of ovalbumin (OVA) during the sensitization stage is considered a crucial factor in the development of airway hyperresponsiveness (AHR). However, the inconsistent dosages of sensitizing OVA used in current studies and the lack of research on their impact on AHR are notable limitations.MethodsWe examined the impact of increasing sensitizing doses of OVA in a murine asthma model, which entailed initial sensitization with OVA followed by repeated exposure to OVA aerosols. BALB/c mice were primed with doses of OVA (0, 10, 20, 50, and 100 μg) plus 1 mg Alum on Days 0 and 7, and were challenged with OVA aerosols (10 mg/mL for 30 min) between Days 14 and 17. Antigen‐induced AHR to methacholine (MCh), as well as histological changes, eosinophilic infiltration, and epithelial injury were assessed.ResultsThe result indicated that there are striking OVA dose‐related differences in antigen‐induced AHR to MCh. The most intense antigen‐induced AHR to MCh was observed with sensitization at 50 μg, while weaker responses were seen at 10, 20, and 100 μg. Meanwhile, there was a significant increase in eosinophil count with sensitization at 50 μg. The changes of AHR were correlated with total cells count, lymphocytes count, eosinophils count, and basophils count in bronchoalveolar lavage fluid; however, it did not correlate with histological changes such as cellular infiltration into bronchovascular bundles and goblet cell hyperplasia of the bronchial epithelium.ConclusionOverall, this study demonstrated that sensitization with 50 μg of OVA resulted in the most significant AHR compared to other dosages. These findings may offer valuable insights for future research on mouse asthma modeling protocols.

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Different Phenotypes in Asthma: Clinical Findings and Experimental Animal Models

Cited by 14 publications

References 205 publications

TIPE2 May Target the Nrf2/HO-1 Pathway to Inhibit M1 Macrophage–Related Neutrophilic Inflammation in Asthma

TIPE2 May Target the Nrf2/HO-1 Pathway to Inhibit M1 Macrophage–Related Neutrophilic Inflammation in Asthma

How the Immune System Responds to Allergy Immunotherapy

Effects of increasing sensitizing doses of ovalbumin on airway hyperresponsiveness in asthmatic mice

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