Comparative responses to nasal allergen challenge in allergic rhinitic subjects with or without asthma

<p>Abstract</p> <p>Background</p> <p>Nasal allergen challenge (NAC) is useful to study the pathophysiology of rhinitis, and multiple challenges may more adequately approximate natural exposure.</p> <p>Objective</p> <p>To determine the effect of 4 consecutive daily NAC, on clinical and inflammatory parameters in rhinitics with or without asthma.</p> <p>Methods</p> <p>Rhinitic subjects were recruited: 19 with mild asthma and 13 without asthma. Subjects underwent a control challenge (normal saline) followed by 4 consecutive daily NAC. Allergen challenge consisted of spraying the chosen allergen extract into each nostril until a positive nasal response occurred. Symptoms were recorded on a Likert scale, and oral peak expiratory and nasal peak inspiratory flows allowed assessment of a nasal blockage index (NBI), for a period of 7 hours. Induced sputum and nasal lavage were performed on control day and after 1 and 4 days of NAC.</p> <p>Results</p> <p>Compared with the control day, there was a significant increase in symptom scores and NBI 10 minutes after each last daily NAC in both groups (p < 0.05). Symptom scores and NBI were similar for the 2 groups, except for nasal obstruction and rhinorrhea, which were more marked in subjects with asthma and rhinitis, respectively. Nasal lavage eosinophils were increased after 4 days of challenges in both groups, but there was no change in sputum eosinophils. No cumulative effect or any late response were observed in any of the groups over the challenge period.</p> <p>Conclusion</p> <p>Multiple NAC may be a useful tool to study the pathophysiology of allergic rhinitis or its relationships with asthma.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01286129">NCT01286129</a></p

Cord blood hemopoietic progenitor cell toll like receptor expression and function: a mechanism underlying allergic inflammation in early life?

RATIONALE: Neonatal immune responses to environmental stimuli, mediated via TLR, may determine the development of atopy in childhood. Since hemopoietic mechanisms are involved in development and maintenance of allergic inflammation, we investigated alterations in progenitor expression and differentiation profiles after stimulation with TLR agonists.&lt;p&gt;&lt;/p&gt; METHODS: Freshly isolated, CD34-enriched human CB cells were stimulated with 10μg/mL lipopolysaccharide (LPS) or 5μM CpG ODN overnight. Flow cytometric analyses were used to evaluate surface and intracellular expression of TLR-2, TLR-4, TLR-9, as well as the hemopoietic cytokine receptors (HCR) IL-5R, IL-3R and GM-CSFR; methylcellulose cultures were performed to assess CD34+ cell differentiation capacity into Eo/B CFU.&lt;p&gt;&lt;/p&gt; RESULTS: After TLR agonist stimulation, CD34+ cell TLR-2, -4 and TLR-9 percentage expression increased significantly (p=0.005), whereas HCR expression decreased (p=0.01); however, mean fluorescence intensity of all receptors was found to be increased. Stimulation with a combination of TLR agonists and hemopoietic cytokines induced increased IL-5- and IL-3-responsive Eo/B CFU (p=0.02), when compared to hemopoietic cytokine stimulation alone.&lt;p&gt;&lt;/p&gt; CONCLUSIONS: CB CD34+ progenitor cells significantly express TLR, and TLR ligation directly affects both TLR and HCR expression. These receptor alterations allow modulation of progenitor cell differentiation capacity into eosinophils and basophils, key cells involved in allergic inflammation. These findings may highlight an alternate innate immune pathway of microbial influence on the development of allergic inflammation in early life.&lt;p&gt;&lt;/p&gt

In Vitro Effects of Budesonide on Eosinophil-Basophil Lineage Commitment

IL-5 is the primary cytokine that stimulates the production and survival of eosinophils and basophils from progenitor cells. The inhaled glucocorticoid, budesonide, has been shown to exert a therapeutic effect via suppression of eosinophil/basophil progenitors in vivo. Since various steroids have exhibited the ability to enhance eosinophil/basophil progenitor differentiation, we examined the effects of budesonide in vitro. Bone marrow and cord blood samples were obtained and cultured in the presence of IL-5 alone or IL-5 plus budesonide. Eosinophil/basophil colony-forming units were enumerated from cultured nonadherent mononuclear cells and from purified CD34+ cells. CD34+ cells with and without budesonide were also examined for up-regulation of ERK1/2, MAPK and GATA-1 using real time-PCR. Results: i) up-regulation of eosinophil/basophil colony-forming units is due to the direct effects of budesonide on IL-5-stimulated progenitors; ii) GATA-1 is likely involved in the early amplification of eosinophil/basophil progenitor commitment leading to increased differentiation. A potential transcriptional pathway has been identified which may mediate the effects of budesonide on eosinophil/basophil lineage commitment

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Toll-like receptor-mediated eosinophil-basophil differentiation: autocrine signalling by granulocyte-macrophage colony-stimulating factor in cord blood haematopoietic progenitors

Summary Eosinophils are multi-functional leucocytes that play a role in inflammatory processes including allergy and infection. Although bone marrow (BM) inflammatory cells are the main source of eosinophil-basophil (Eo/B) differentiation-inducing cytokines, a recent role has been demonstrated for cytokine induction through Toll-like receptor (TLR)-mediated signalling in BM progenitors. Having previously demonstrated that cord blood (CB) progenitors induce Eo/B colony-forming units (CFU) after lipopolysaccharide (LPS) stimulation, we sought to investigate the intracellular mechanisms by which LPS induces Eo/B differentiation. Freshly isolated CD34-enriched human CB cells were stimulated with LPS (and/or pharmacological inhibitors) and assessed for alterations in haematopoietic cytokine receptor expression and signalling pathways by flow cytometry, Eo/B CFU in methylcellulose cultures, and cytokine secretion using Luminex assays. The LPS stimulation resulted in a significant increase in granulocyte-macrophage colony-stimulating factor (GM-CSF)-responsive, as opposed to interleukin-5-responsive, Eo/B CFU, which also correlated with significant increases in CD34 + cell GM-CSFRa expression. Functionally, CB CD34 + cells secrete abundant amounts of GM-CSF following LPS stimulation, via a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism; this secretion was responsible for Eo/B CFU formation ex vivo, as shown by antibody blockade. We show for the first time that LPS stimulation of CB progenitor cells results in autocrine activation of p38 MAPK-dependent GM-CSF secretion facilitating Eo/B differentiation ex vivo. This work provides evidence that early life exposure to products of bacterial agents can modulate Eo/B differentiation, representing a novel mechanism by which progenitor cells can respond to microbial stimuli and so affect immune and inflammatory responses

Circulating dendritic cells and asthma: Rapid changes following inhaled allergen

Dendritic cells (DC) are thought to play a key role in the initiation and maintenance of T-cell immunity to inhaled antigens. DC density within the bronchial mucosa is increased in stable asthma, and we previously showed a significant reduction in numbers of circulating DC within 24 hours of allergen inhalation (AJRCCM 1998;157: A871). However, the kinetics of this DC response is not clear. Using flow cytometry, we enumerated absolute numbers of blood DC and other leukocytes in 9 mild asthmatics, before and after allergen challenge. Data are expressed as a percentage of baseline values prior to allergen challenge (*p < 0.05 versus baseline). 3h 6h 24h post challenge Dendritic cells 63.1 ±20.3* 62.8±17.2* 78.0±22.2* Lymphocytes 87.1 ±15.1* 75.4±14.1* 88.6±13.5* Monocytes 95.0±12.6 98.5±25.9 99.5±10.5 Eosinophils 82.1±28.2 71.6±24.6* 117.3±24.5 Granulocytes 116.6±28.4 116.3±34.9 80.3±11.2* We conclude that allergen challenge is associated with rapid reductions in numbers of circulating DC and lymphocytes, whereas changes in other circulating leukocytes occurred more slowly (eosinophils & granulocytes), or were not detectable (monocytes). These findings imply that margination of circulating DC and subsequent recruitment into the airways is initiated very rapidly following allergen inhalation