Goblet Cell Hyperplasia Research Articles

Dioscin exhibits protective effects on in vivo and in vitro asthma models via suppressing TGF-β1/Smad2/3 and AKT pathways.

Dioscin is a natural product that possesses protective effects on multiple chronic injuries, but its effects on asthma are not fully understood. Herein, we evaluated its effects on asthmatic mice established by ovalbumin (OVA) sensitization and challenges and further explored the mechanism. Inflammatory cells in bronchoalveolar lavage fluids (BALFs) were analyzed using Diff-Quik staining. OVA-specific immunoglobulin E (IgE)/IgG1in serum and inflammatory cytokines (interleukin 4[IL-4], IL-5, IL-13, and tumor necrosis factor-α) in BALFs and lung tissues were measured using Enzyme-Linked Immunosorbent Assay Kits. Hematoxylin and eosin, periodic acid-Schiff, and immunohistochemistry staining showedhistopathological changes in lung tissues. Epithelial-mesenchymal transition (EMT) in human bronchial epithelial (16HBE) cells was assessed by immunofluorescence staining. Hydroxyproline content was used to evaluate collagen deposition. Polymerase chain reaction and Western blot were performed to measure messenger RNA and protein expression. We found that dioscin treatment (particularly at the dose of 80 mg/kg) significantly inhibited pulmonary inflammation in asthmatic mice, as evidenced by the decreased serum OVA-specific IgE/IgG1 and the reduced inflammatory cells and cytokines in BALFs and lung tissues. Moreover, dioscin effectively ameliorated the goblet cell hyperplasia, mucus hypersecretion, collagen deposition, and smooth muscle hyperplasia in the airways of asthmatic mice. Mechanistically, dioscin restrained the activated TGF-β1/Smad2/3 and protein kinase B(AKT) signal pathways in lung tissues and potently reversed the TGF-β1-induced EMT and phosphorylation of Smad2/3 and AKT in 16HBE cells. Collectively, dioscin displayed protective effects on OVA-induced asthmatic mice via adjusting TGF-β1/Smad2/3 and AKT signal pathways, supporting the fact that dioscin could be a candidate for chronic asthma prevention in the future.

Immunomodulatory Effect of SINA 1.2 Therapy Protocol in Asthmatic Mice Model: A Combination of Oxymel and Sauna.

Alternative medicine, has become popular in asthmatic patients. We evaluated the immunomodulatory effects of SINA 1.2 therapy protocol derived from Persian medicine in an asthmatic mice model. Forty-two male BALB/c mice divided into six groups: one control (sham) and five sensitized groups (by parenteral injection of 20 μg ovalbumin in 100 μL normal saline plus 50 μL alum on days 1 and 14). Sensitized groups were as: untreated, budesonide (1 mg nebulized budesonide: 200 μg/puff every 5 min for 25 min), dry sauna (30 min, 37°C), oral oxymel (gavaged: 0.2 mL of the syrup plus 0.8 mL of water), and SINA protocol No.1.2 (oxymel followed by sauna) groups. Treatments were given for 10 days from day 23 to 33 then sacrificed. Significant gene expression reduction of interleukin(IL)-4, IL-5, and MUC5AC and increase of interferon(IFN)-γ and IFN-γ/IL-4 ratio and decreased perivascular and peribronchial inflammation, goblet cell hyperplasia, and subsequent mucus hypersecretion in SINA group were seen compared to untreated group. SINA lowered IL-5 and MUC5AC gene expression levels similar to the budesonide and acted better than budesonide in increasing IFN-γ gene expression up to normal level. Compared with the asthma group, sauna alone only affected MUC5AC and IFN-γ gene expressions and oxymel alone, only reduced IL-4 gene expression, perivascular and peribronchial inflammation, and mucus hypersecretion. It seems that SINA therapy alleviates asthma via immune modulation of pro-inflammatory cytokines and improvement of pathological changes in ovalbumin-induced asthma in mice, supporting the notion of innate healing power mentioned in Persian medicine literature.

Study Effect of Azithromycin and Doxycycline in Mucus Producing and Inflammatory Signaling Pathways of Allergic Asthma.

Asthma is a respiratory disease; involving millions of people worldwide. The main cause of asthma is allergy and immune response dysregulation. The effects of azithromycin and doxycycline as asthma-controlling drugs were evaluated in this study. Mice asthma model was produced and asthmatic mice were treated with azithromycin (75 mg/kg, orally) and doxycycline (20 mg/kg, orally). Eosinophils and neutrophils count, interleukin (IL)-4, IL-5, IL-12, IL-13, and total immunoglobulin E (IgE) levels were measured. Histological study and evaluating the genes expression of Muc5ac, Muc5b, IL-33, COX2, MYD88, and TRAF6 were performed. Azithromycin and doxycycline did not affect eosinophil and neutrophil percentage, IL-4, IL-5, IL-12, and total IgE levels, peribronchial and perivascular inflammation, goblet cell hyperplasia, and gene expression of MYD88, TRAF6, and COX2. Treatment with azithromycin significantly decreased IL-13 level, mucus secretion, and gene expression of IL-33, Muc5ac, and Muc5b; compared to the non-treated asthma group. Azithromycin administration controls mucus secretion and inflammation. Azithromycin therapy and not doxycycline might be an effective adjuvant option in asthma with reducing mucus in the airway.

Bronchodilatory effect of higenamine as antiallergic asthma treatment

Asthma is a complex airway disease that affects more than 350 million humans worldwide. Allergic asthma symptoms are induced by Th2 immune response with the release of cytokines and allegro-inflammatory...

HOIL1 regulates group 2 innate lymphoid cell numbers and type 2 inflammation in the small intestine

Patients with mutations in HOIL1 experience a complex immune disorder including intestinal inflammation. To investigate the role of HOIL1 in regulating intestinal inflammation, we employed a mouse model of partial HOIL1 deficiency. The ileum of HOIL1-deficient mice displayed features of type 2 inflammation including tuft cell and goblet cell hyperplasia, and elevated expression of Il13, Il5 and Il25 mRNA. Inflammation persisted in the absence of T and B cells, and bone marrow chimeric mice revealed a requirement for HOIL1 expression in radiation-resistant cells to regulate inflammation. Although disruption of IL-4 receptor alpha (IL4Rα) signaling on intestinal epithelial cells ameliorated tuft and goblet cell hyperplasia, expression of Il5 and Il13 mRNA remained elevated. KLRG1hi CD90lo group 2 innate lymphoid cells were increased independent of IL4Rα signaling, tuft cell hyperplasia and IL-25 induction. Antibiotic treatment dampened intestinal inflammation indicating commensal microbes as a contributing factor. We have identified a key role for HOIL1, a component of the Linear Ubiquitin Chain Assembly Complex, in regulating type 2 inflammation in the small intestine. Understanding the mechanism by which HOIL1 regulates type 2 inflammation will advance our understanding of intestinal homeostasis and inflammatory disorders and may lead to the identification of new targets for treatment.

Interval appendicitis shows histological differences from acute appendicitis and may mimic Crohn disease and other forms of granulomatous appendicitis.

While patients presenting with clinical signs and symptoms of acute appendicitis (AA) often receive surgical intervention shortly after presentation, certain patients may instead receive non-operative management initially, with appendectomy later. The histology of such interval appendicitis (IA) has only been described in small series. Also, we have noticed a recent increase in the incidence of IA specimens at our institution. We identified appendectomy specimens in our department during 2018 with available haematoxylin and eosin slides and electronic clinical data, and evaluated multiple histological findings. Cases were then divided into AA and IA, based on clinical history (AA if the patient presented to the hospital within 1 week of symptom onset and underwent appendectomy within 48 h; IA if appendectomy was delayed at least 1 week). Changes between groups were compared. The cohort included 165 cases (125 AA, 40 IA). Findings significantly more common in AA included mucosal acute inflammation, mural acute inflammation and acute serositis. Findings significantly more common in IA included Crohn-like mural inflammation, mural fibrosis, goblet cell hyperplasia, granulomas, xanthogranulomatous inflammation, haemosiderin-laden macrophages and granulation tissue. The rate of IA in 2018 (24%) was noticeably higher than in previous years. Acute inflammatory changes are more common in AA but can remain present in IA. Mural fibrosis, serosal adhesions, haemosiderin-laden macrophages and granulation tissue suggest IA. Granulomas and xanthogranulomatous inflammation can also be seen in IA, and Crohn-like mural inflammation is not uncommon. These histological patterns can guide signout and prevent diagnostic errors, particularly when clinical information is unavailable.

Orally Administered Fisetin Reduces the Symptoms of Acute Allergic Asthma in a Preclinical Mouse Model

Background: Asthma is a very common, non-communicable, chronic respiratory disease, with a high incidence rate worldwide. Currently, no permanent therapeutic strategies are available for the treatment of asthma. Drugs, such as corticosteroids, β2-agonists, and anticholinergics, only temporarily reduce symptoms and have various adverse effects. In this study, we investigated the use of fisetin, a readily available natural product found in fruits, such as strawberries and apples, to treat acute asthma in a preclinical mouse model. Methods: We induced asthma in BALB/c mice using intraperitoneal sensitization and repeated intratracheal challenges with ovalbumin (Ova), followed by oral administration of 0.6 mg/kg (MPK) aqueous fisetin (primary stock in DMSO) before each intratracheal challenge. The mice were subsequently evaluated with whole-body plethysmography, 24 hours after the last intratracheal challenge, to measure airway hyper-responsiveness (AHR). The mice were sacrificed, and their tissues removed to evaluate a range of disease parameters. Results: In mice treated with fisetin, AHR was significantly reduced, as shown by plethysmography. Acute inflammation associated with asthma was also reduced, as determined by inhibition of cellular infiltration, serum IgE, and serum nitric oxide (NO), as well as a reduction in goblet cell hyperplasia. We also found that fisetin potentially acts by blocking the TH2 response, including pro-inflammatory signaling molecules such as NFκB, STAT6, HIF1α, iNOS, TNFα and IL13. Conclusion: Our study showed that a low dose of fisetin (50 nM), administered orally in an aqueous solution, may offer a safe and economical therapeutic strategy for asthma.

Amelioration of Ovalbumin-Induced Allergic Asthma by Juglans regia via Downregulation of Inflammatory Cytokines and Upregulation of Aquaporin-1 and Aquaporin-5 in Mice.

Juglans regia (J. regia) has been used traditionally to treat cough and asthma. The present study evaluates the immunomodulatory and anti-inflammatory potential of J. regia against ovalbumin (OVA)-induced allergic asthma. Intraperitoneal sensitization proceeded by intranasal challenge with OVA was used to induce allergic asthma. BALB/c mice were treated with methanol, n-hexane, and ethyl acetate extracts of J. regia and methylprednisolone one week after 2nd sensitization with OVA and continued for 7 days. mRNA expression levels of IL-4, IL-5, IL-13, AQP-1, AQP-5 TNF-α, TGF-β, and NF-kB were determined using reverse transcription polymerase chain reaction. Hematoxylin and eosin, and periodic acidic-Schiff stains were used for histopathological studies of lung tissues. The data presented all three extracts of J. regia significantly ameliorated airway inflammation by reducing expression levels of IL-4, IL-5, and IL-13 and TNF-α in OVA-treated mice. The suppression of goblet cells hyperplasia and inflammatory cells infiltration by J. regia involved low TGF-β and NF-kB levels. Pretreatment with J. regia also increased the AQP-1 and AQP-5 expression levels in mice treated with OVA. This study supported the traditional use of J. regia and proposed that J. regia ameliorated allergic asthma by suppression of proinflammatory cytokines and elevation of AQP-1 and AQP-5 expression levels.

Fructus Amomi extract attenuates nasal inflammation by restoring Th1/Th2 balance and down-regulation of NF-κB phosphorylation in OVA-induced allergic rhinitis.

Fructus Amomi Cardamomi (FA) is the mature fruit of Amomum villosum Lour (family Zingiberaceae) and is commonly used in Chinese traditional medicine to treat various gastrointestinal disorders. FA’s possible benefits as an allergic rhinitis (AR) treatment, however, have not been examined. We used an ovalbumin (OVA)-induced AR mouse model to identify any anti-allergic effects associated with the administration of 200 mg/kg FA or dexamethasone (Dex) 2.5 mg/kg by oral administration. The results of our testing confirm that FA ameliorated nasal symptoms and alleviated nasal epithelium swelling, reduced the goblet cell hyperplasia and eosinophil cell infiltration in the nasal epithelium, and inhibited lung tissue inflammation and Dex as well. Significantly decreased Th2 cytokine (interleukin (IL)-1β, IL-4, and IL-5) expression, and a correspondingly significant increase in Th1 cytokine (IL-12, interferon (IFN)-γ) production, was observed in nasal lavage fluid (NALF) taken from mice that received FA or Dex treatment. FA also reduced the presence of OVA-specific immunoglobulin (Ig) E, OVA-specific IgG1, and histamine levels in serum, and inhibited mast cell degranulation in vitro. In addition, these effects were involved with the reduction in NF-κB phosphorylation. These results suggest that FA restores Th1/Th2 balance and inhibits NF-κB phosphorylation and mast cell degranulation, thereby achieving a notable anti-inflammatory effect. Accordingly, it has the potential to be used as an efficacious therapeutic treatment for AR.

Study effect of probiotics and prebiotics on treatment of OVA-LPS-induced of allergic asthma inflammation and pneumonia by regulating the TLR4/NF-kB signaling pathway

Asthma is a common respiratory disease, and immune system dysregulation has direct relevance to asthma pathogenesis. Probiotics and prebiotics have immunomodulatory effects and can regulate immune responses and may attenuate allergic reactions. Therefore, in this study, we explored the role of probiotics and prebiotics in regulating acute airway inflammation and the TLR4/NF-kB pathway. Allergic asthma model of BALB/c mice was produced and treated with probiotics (LA-5, GG, and BB-12) and prebiotics (FOS and GOS). Then AHR, BALF cells count, EPO activity, IL-4, 5, 13, 17, 25, 33, as well as IFN-γ, total and OVA-specific IgE, IgG1, Cys-LT, LTB4, LTC4, and TSLP levels were measured. Also, the GTP/GOT assay was performed and gene expression of Akt, NLR3, NF-kB, PI3K, MyD88, TLR4, CCL11, CCL24, MUC5a, Eotaxin, IL-38, and IL-8 were determined. Finally, lung histopathological features were evaluated. Treatment with probiotics could control AHR, eosinophil infiltration to the BALF and reduce the levels of immunoglobulins, IL-17, GTP and also decrease mucus secretion, goblet cell hyperplasia, peribronchial and perivascular inflammation and also, EPO activity. It could reduce gene expression of TLR4 and CCL11. On the other hand, IL-38 gene expression was increased by both probiotic and prebiotic treatment. Treatment with probiotics and prebiotics could control levels of IL-4, 5, 13, 25, 33, leukotrienes, the gene expression of AKT, NLR3, NF-κB, MyD88, MUC5a. The prebiotic treatment could control peribronchial inflammation and PI3K gene expression. Both of the treatments had no significant effect on the GOT, TSLP and IL-8, eotaxin and CCL24 gene expression. Probiotics and prebiotics could induce tolerance in allegro-inflammatory reactions and alter immune responses in allergic conditions. Probiotics could also modulate cellular and humoral immune responses and prevent allergic disorders.

Polystichum braunii ameliorates airway inflammation by attenuation of inflammatory and oxidative stress biomarkers, and pulmonary edema by elevation of aquaporins in ovalbumin-induced allergic asthmatic mice.

Asthma is a chronic inflammation of pulmonary airways associated with bronchial hyper-responsiveness. The study was aimed to validate the folkloric use of Polystichum braunii (PB) against ovalbumin (OVA)-induced asthmatic and chemical characterization OF both extracts. Allergic asthma was developed by intraperitoneal sensitization with an OVA on days 1 and 14 followed by intranasal challenge. Mice were treated with PB methanolic (PBME) and aqueous extract (PBAE) orally at 600, 300, and 150mg/kg and using dexamethasone (2mg/kg) as standard from day 15 to 26. High performance liquid chromatography-diode array detector analysis revealed the presence of various bioactive compounds such as catechin, vanillic acid, and quercetin. The PBME and PBAE profoundly (p < 0.0001-0.05) declined immunoglobulin E level, lungs wet/dry weight ratio, and total and differential leukocyte count in blood and bronchial alveolar lavage fluid of treated mice in contrast to disease control. Histopathological examination showed profoundly decreased inflammatory cell infiltration and goblet cell hyperplasia in treated groups. Both extracts caused significant (p < 0.0001-0.05) diminution of IL-4, IL-5, IL-13, IL-6, IL-1β, TNF-α, and NF-κB and upregulation of aquaporins (1 and 5), which have led to the amelioration of pulmonary inflammation and attenuation of lung edema in treated mice. Both extracts profoundly (p < 0.0001-0.05) restored the activities of SOD, CAT, GSH and reduced the level of MDA dose dependently. Both extracts possessed significant anti-asthmatic action mainly PBME 600mg/kg might be due to phenols and flavonoids and could be used as a potential therapeutic option in the management of allergic asthma.

PlexinD1 Deficiency in Lung Interstitial Macrophages Exacerbates House Dust Mite-Induced Allergic Asthma.

Interstitial macrophages (IMs) are key regulators of allergic inflammation. We previously showed that the absence of semaphorin 3E (Sema3E) exacerbates asthma features in both acute and chronic asthma models. However, it has not been studied whether Sema3E, via its receptor plexinD1, regulates IM function in allergic asthma. Therefore, we investigated the role of plexinD1 deficiency on IMs in allergic asthma. We found that the absence of plexinD1 in IMs increased airway hyperresponsiveness, airway leukocyte numbers, allergen-specific IgE, goblet cell hyperplasia, and Th2/Th17 cytokine response in the house dust mite (HDM)-induced allergic asthma model. Muc5ac, Muc5b, and α-SMA genes were increased in mice with Plxnd1-deficient IMs compared with wild-type mice. Furthermore, plexinD1-deficient bone marrow-derived macrophages displayed reduced IL-10 mRNA expression, at both the baseline and following HDM challenge, compared with their wild-type counterpart mice. Our data suggest that Sema3E/plexinD1 signaling in IMs is a critical pathway that modulates airway inflammation, airway resistance, and tissue remodeling in the HDM murine model of allergic asthma. Reduced IL-10 expression by plexinD1-deficient macrophages may account for these enhanced allergic asthma features.

The anti-inflammatory effect of dapsone on ovalbumin-induced allergic rhinitis in balb/c mice

AimsAllergic rhinitis (AR), a major chronic inflammatory disease of the respiratory system, is a public health issue because of its substantial negative impact on quality of life and work efficiency alongside its high prevalence and costs. Dapsone is a sulfone chemical with reported anti-inflammatory and antibacterial properties. Accordingly, we investigated the anti-inflammatory impact of dapsone on ovalbumin-induced allergic rhinitis in balb/c mice. Main methodsIntraperitoneal ovalbumin and hydroxide aluminum injection followed by intranasal ovalbumin administration sensitized female Balb/c mice. Mice received intraperitoneal dapsone either acute (5, 10, 20 mg/kg) 30 min before the last ovalbumin challenge, or chronic (20 mg/kg) on days 21 to 35. Key findingsBoth acute and chronic intraperitoneal usage of dapsone showed a considerable decrease in the nasal scratching behavior, the number of sneezing, serum IL-4 and IgE levels of ovalbumin-induced AR in balb/c mice, but there was a significant increase in serum IFNγ level. Histopathological analysis demonstrated a significant reduction of eosinophil numbers, following dapsone injection. Goblet cell hyperplasia and respiratory epithelial-thickness decreased significantly in the acute and chronic 20 mg/kg dapsone groups compared to the ovalbumin-induced controls. SignificanceThis study shows that there is an association between acute and chronic dapsone treatment and some anti-allergic effects through an inflammation cascade.

A56 TUFT CELL RESPONSES DURING ACUTE- AND LATE-STAGE GIARDIA INFECTION

BackgroundEpithelial tuft cells can detect and respond to enteric infections and appear to help clear some intestinal parasites. Through tuft cell luminal surface receptors, tuft cells can sense ligands directly supplied by a parasite, or indirectly via excretory/secretory products. We hypothesize that microbiome alterations may also modulate tuft cell-derived gut responses. Tuft cells release the alarmin cytokine IL-25 which, upon acting on type 2 innate lymphoid cells (ILC2), ultimately lead to tuft and goblet cell hyperplasia. Upon helminth infections, tuft and goblet cell hyperplasia occurred concurrently, and coincided with the peak of infection. The role of tuft cells in infections with the enteric protozoan parasite Giardia sp. is unknown. The aim of our study is to characterize how tuft cells may be implicated in the pathophysiology of giardiasis, in an attempt to uncover novel regulatory pathways of intestinal physiology.AimsIn this study, we aim to characterise the tuft cell response to Giardia infection during acute and late stages of infection and to assess goblet cell hyperplasia.Methods5–7-week-old C57BL/6 mice and tuft cell-deficient mice ( Pou2f3-/-) were orally gavaged with 5x104Giardia muris trophozoites and scarified at days 4, 11 and 21 post-infection. Parasite burden was assessed in the duodenum. Immunofluorescence (IF) staining of doublecortin-like kinase 1 (DCLK1) – a marker of tuft cells – was performed on C57BL/6 mice jejunum tissue sections and the number of tuft cells was quantified. Goblet cells were quantified in PAS/AB-stained jejunum sections. Quantitative PCR (qPCR) was performed on Dclk1, the epithelial secretory cell transcription factor Atoh1, and the mucus gene Muc2.Results G. muris infected C57BL/6 mice displayed high parasite load at days 4 ( p<0.05) and 11 ( p<0.05), with no or low parasite burden at day 21 ( p<0.05). Pou2f3-/- mice showed less robust parasite burden at days 4 and 11, and similar low parasite burden at day 21, compared to WT mice. At day 21, tuft cell (DCLK1+) counts ( p<0.05) and Dclk1 mRNA expression levels were increased in Giardia infected mice in the jejunum. Goblet cell number and Atoh1 and Muc2 expression were increased at day 4 post-infection.ConclusionsThe data demonstrate that tuft cells expand late in Giardia infection, suggesting that upon parasite infection, tuft cells may possess roles in tissue repair or clearance of infection. Tuft cell-deficient mice ( Pou2f3-/-) had lower parasite burden early in Giardia infection, counter-intuitively suggesting that tuft cells may facilitate trophozoite colonization, further highlighting the novelty of these findings. The crosstalk between tuft cells, Giardia, and other host responses during acute and late stages of infection remain to be fully characterised.Funding AgenciesNSERC

A232 TUFT CELLS COORDINATE RAPID EXPULSION OF THE TAPEWORM H. DIMINUTA BUT ARE NOT REQUIRED FOR ENHANCED IMMUNITY AGAINST THE NEMATODE, H. POLYGYRUS, IN MICE PREVIOUSLY INFECTED WITH H. DIMINUTA

BackgroundThe tuft cell is an important sentinel that monitors the gut lumen and coordinates immunity against parasitic nematodes. We showed small intestinal tuft cell hyperplasia 11 days post-infection (dpi.) with the tapeworm Hymenolepis diminuta: a time when the parasite is no longer present in murine hosts. This may be a way by which the host protects itself from subsequent helminth-infections, a common phenomenon in parasite-endemic world regions. We test this supposition using Pou2f3-/- mice that lack tuft cells.AimsTo test the hypothesis that tuft cells are important in the anti-worm response in H. diminuta ( H.d.)-infected mice subsequently infected with the nematode parasite Heligosomoides polygyrus ( H.p.).MethodsMale C57BL6 and Pou2f3-/- mice (8–12 weeks) were infected with 5 H.d. cysticercoids ± 200 H.p. larvae at 10 dpi with H. diminuta (non H.p. mice - control). Upon necropsy at 24 dpi H. diminuta (i.e. 14 dpi H.p. in co-infected mice), both worms were ennumerated in small intestinal washings, H.p. granulomas examined and fecal egg counts performed. Small intestinal segments were stained for tuft (DCLK1+) and goblet cells (PAS+). As a surrogate of successful infection, IL-4 and IL-10 were measured in supernatants from concanavalin-A treated splenocytes.ResultsWild-type (WT) mice expel H. diminuta by 11 dpi and this was delayed in Pou2f3-/-mice, with worms readily detectable at 14 dpi and absent by 21 dpi. Despite the delayed expulsion, both WT and Pou2f3-/- mice showed increased splenic production of IL-4 and IL-10; however, unlike WT mice, H. diminuta-infected Pou2f3-/- mice show no increase in jejunal goblet cell numbers. Mice infected with H. diminuta displayed a degree of increased resistance to H.p.-infection defined by reduced worm and egg burdens, and increased granuloma formation in comparison to H.p.-only infected animals. In this sequential co-infection model, there were no significant differences between WT and Pou2f3-/- mice in the response to H.p.ConclusionsThe absence of tuft cells slows expulsion of H. diminuta from its non-permissive mouse host and correlates with diminished goblet cell hyperplasia. Hypothesizing that H. diminuta-evoked tuft cell hyperplasia would enhance the immune response to a subsequent infection with an unrelated nematode parasite proved incorrect. While H. diminuta-infected mice were partially protected from H.p., response was similar in WT and Pou2f3-/- mice. Thus tuft cells are important in worm detection: yet, our co-infection data suggests that other events initiated by the primary worm infection impact the outcome of subsequent infection with a different helminth and tuft cells have a limited, if any, role to play in this helminth-host-helminth interaction.Funding AgenciesCIHRNSERC, Eye’s High International doctoral scholarship

Effect of Loaded Glycyrrhizic Acid on PLGA Nano-particle on Treatment of Allergic Asthma.

Asthma is considered a complex disease of the respiratory system that is characterized by bronchoconstriction, airway inflammation, cough, dyspnea, and wheezing. Allergic reactions are the main reason behind asthma which is known as an important health problem with a high rate of morbidity and mortality in patients with respiratory diseases. Liquorice, the root of Glycyrrhiza, is primarily effective for asthma which is widely used in herbal medicine. In the present study, we designed nano-particles that carry Glycyrrhizic acid as the effective component of Liquorice. After Poly (D,L-lactide-co-glycolic acid) PLGA nanoparticle preparation and Glycyrrhizic acid loading, the morphology of the nanoparticle, the electric charge distribution, and drug-releasing ability were studied. Then the effect of Glycyrrhizic acid-PLGA on the animal model of allergic asthma was investigated. Glycyrrhizic acid-nanoparticle had a mean±SD size of 350±50 nm. about 67% of the effective component was released after 10 h. The interleukin (IL)-4, IL-5, IL-13, and IL-25 levels and the Muc5ac mRNA expression were decreased in the Glycyrrhizic acid-PLGA treated group. In addition, a significant decline was observed in goblet cell hyperplasia, mucus hyper-secretion, and eosinophilic inflammation around bronchi and vessels of the nano-drug treated group, compared with the asthmatic group. We found that Glycyrrhizic acid-PLGA nanoparticle had an anti-asthma effect which may be used as a new drug to cure asthma. It can prevent bronchial obstruction, breathlessness, and asthma attacks.

IL13Pred: A method for predicting immunoregulatory cytokine IL-13 inducing peptides

BackgroundInterleukin 13 (IL-13) is an immunoregulatory cytokine, primarily released by activated T-helper 2 cells. IL-13 induces the pathogenesis of many allergic diseases, such as airway hyperresponsiveness, glycoprotein hypersecretion, and goblet cell hyperplasia. In addition, IL-13 inhibits tumor immunosurveillance, leading to carcinogenesis. Since elevated IL-13 serum levels are severe in COVID-19 patients, predicting IL-13 inducing peptides or regions in a protein is vital to designing safe protein therapeutics particularly immunotherapeutic. ObjectiveThe present study describes a method to develop, predict, design, and scan IL-13 inducing peptides. MethodsThe dataset experimentally validated 313 IL-13 inducing peptides, and 2908 non-inducing homo-sapiens peptides extracted from the immune epitope database (IEDB). A total of 95 key features using the linear support vector classifier with the L1 penalty (SVC-L1) technique was extracted from the originally generated 9165 features using Pfeature. These key features were ranked based on their prediction ability, and the top 10 features were used to build machine learning prediction models. Various machine learning techniques were deployed to develop models for predicting IL-13 inducing peptides. These models were trained, tested, and evaluated using five-fold cross-validation techniques; the best model was evaluated on an independent dataset. ResultsOur best model based on XGBoost achieves a maximum AUC of 0.83 and 0.80 on the training and independent dataset, respectively. Our analysis indicates that certain SARS-COV2 variants are more prone to induce IL-13 in COVID-19 patients. ConclusionThe best performing model was incorporated in web-server and standalone package named ‘IL-13Pred’ for precise prediction of IL-13 inducing peptides. For large dataset analysis standalone package of IL-13Pred is available at (https://webs.iiitd.edu.in/raghava/il13pred/) webserver and over GitHub link: https://github.com/raghavagps/il13pred.

Immunomodulatory and anti-inflammatory effects of Aerva lanata in ovalbumin induced allergic asthmatic mice

Ethnopharmacological relevanceAerva lanata Linn. (A. lanata) is traditionally used for cough, sore throat and asthma. Aim of studyThe aim of the present study was to investigate the immunomodulatory and anti-inflammatory potentials of A. lanata in allergic asthmatic mice. Materials and methodsBALB/c mice were administered with three different (methanol, n-hexane and ethyl acetate) extracts of A. lanata two weeks after immunization with ovalbumin and continued for 7 days. Inflammatory cells count was estimated in blood and broncho-alveolar lavage fluid (BALF). RT-PCR was used to find out mRNA expression levels of inflammatory mediators. GC-MS analysis was also carried out. ResultsAmong three extracts of A. lanata, ethyl acetate extract ameliorated (p < 0.001) count of inflammatory cells both blood and BALF remarkably. This study indicated that ethyl acetate extract of A. lanata lowered (p < 0.001) the level of inflammatory modulator TNF-α and IgE antibodies. A. lanata reduced (p < 0.001) interleukin 4, 5, 13 and enhanced (p < 0.001) expression levels of AQP1 and AQP5 in asthmatic mice. GC-MS analysis of ethyl acetate fraction indicated the presence of various anti-oxidant phyto-constituents. The groups treated with A. lanata improved inflammatory, goblet cells hyperplasia scoring and alveolar thickening. ConclusionsThe anti-asthmatic effect of A. lanata might be contributed by the suppression of edema, pro-inflammatory cytokines and IgE antibodies, and elevation of aquaporin expression levels, suggesting future study and clinical trials to propose it as a candidate to treat allergic asthma. The anti-oxidant phytochemicals present in A. lanata might be responsible for such potential.

Aspergillus fumigatus-Host Interactions Mediating Airway Wall Remodelling in Asthma.

Asthma is a chronic heterogeneous respiratory condition that is mainly associated with sensitivity to airborne agents such as pollen, dust mite products and fungi. Key pathological features include increased airway inflammation and airway wall remodelling. In particular, goblet cell hyperplasia, combined with excess mucus secretion, impairs clearance of the inhaled foreign material. Furthermore, structural changes such as subepithelial fibrosis and increased smooth muscle hypertrophy collectively contribute to deteriorating airway function and possibility of exacerbations. Current pharmacological therapies focused on airway wall remodelling are limited, and as such, are an area of unmet clinical need. Sensitisation to the fungus, Aspergillus fumigatus, is associated with enhanced asthma severity, bronchiectasis, and hospitalisation. How Aspergillus fumigatus may drive airway structural changes is unclear, although recent evidence points to a central role of the airway epithelium. This review provides an overview of the airway pathology in patients with asthma and fungal sensitisation, summarises proposed airway epithelial cell–fungal interactions and discusses the initiation of a tissue remodelling response. Related findings from in vivo animal models are included given the limited analysis of airway pathology in patients. Lastly, an important role for Aspergillus fumigatus-derived proteases in triggering a cascade of damage-repair events through upregulation of airway epithelial-derived factors is proposed.

Suppression of cytokine storm and associated inflammatory mediators by salicylaldehyde derivative of pregabalin: An innovative perspective for alleviating airway inflammation and lung remodeling

ObjectivesPregsal is a novel salicylaldehyde derivative of pregabalin, a structural analogue of gamma-aminobutyric acid approved for treating epilepsy, neuropathic pain and diabetic peripheral neuropathy but not trialled to date for airway inflammatory diseases. The current study evaluated a preclinical model of airway inflammation and lung remodelling induced by ovalbumin (OVA) for the potential benefits of pregsal. MethodsWistar rats (N = 10 per group) were divided into four groups sensitized intraperitoneally (i.p.) and then challenged intranasally with OVA, with or without i.p. pregsal (100 mg/kg) or methylprednisolone (MP) (15 mg/kg). Airway inflammation was assessed through inflammatory cell infiltration in the lungs, delayed-type hypersensitivity (DTH), and nitric oxide (NO) level using bronchoalveolar lavage fluid (BALF) and lung tissues. The mRNA expression levels of a panel of inflammatory mediators (cytokines, chemokine and growth factors) in the lungs were measured by the reverse transcription-polymerase chain reaction (RT-PCR). Systemic inflammation was assessed using splenocyte proliferation and total and differential leucocyte count in blood and BALF. Lung remodelling was assessed by wet/dry lung weight ratio, epithelial thickness and goblet cell hyperplasia, hydroxyproline and osteopontin (OPN) levels, arginase activity in lungs, and ornithine decarboxylase (ODC) activity in lung mitochondria. ResultsPregsal significantly alleviated the total and differential leucocyte count in blood and BALF, NO production in BALF and recruitment of inflammatory cells in the lungs. It suppressed the T-cell response and attenuated the OVA-induced lung epithelial thickness, goblet cell hyperplasia, wet/dry lung weight ratio, hydroxyproline and OPN levels, arginase and ODC activity. Levels of inflammatory mediators were also downregulated in the lungs by pregsal. ConclusionsThe key findings of this study indicate that pregsal significantly reduces the development of airway inflammation and lung remodelling by suppression of cytokine storm and associated inflammatory mediators.