Reduced Mucus Production Research Articles

Effect of Xiaoqinglong decoction on mucus hypersecretion in the airways and cilia function in a murine model of asthma

ObjectiveXiaoqinglong decoction (XQL) has been used in traditional Chinese medicine as a prescription for asthma treatment. We explored the effects of XQL on mucus hypersecretion and ciliophagy in the airways of mice in which asthma had been induced by ovalbumin (OVA). MethodsThirty-six mice were sensitized by OVA injection (i.p.) on day-0 and day-14 and challenged with 1% OVA on day 18–22. Then, they were divided into three groups: model, carbocysteine and XQL. From day-15 to day-22, the XQL group was administered XQL (10 g/kg, p.o.) 1 hour before each aerosol challenge with OVA. To evaluate the effect of XQL on mucus hypersecretion, AB-PAS staining, measurement of serum levels of interleukin (IL)-13, bronchoalveolar lavage fluid (BALF) analyses, ciliophagy analyses, as well as co-expression of Light Chain 3 (LC3) and acetylated α-tubulin by immunofluorescence staining were undertaken. ResultsTreatment with XQL (10 g/kg) attenuated mucus secretion in the airways, and reduced the positive areas of AB-PAS staining in histopathologic lung tissues (P < .05). IL-13 expression in serum (P < .01), OVA-induced inflammatory changes, and the number of white blood cells (P < .01) in BALF samples were also reduced. However, the effect on mucus secretion was less apparent in the carbocysteine group compared with the XQL group. XQL treatment also improved the cilia length and elicited a substantial reduction in ciliophagy and LC3 expression in the tracheal epithelium. ConclusionXQL can attenuate cilia shortening, aid the clearance function of ciliated epithelial cells, and reduce mucus production in an OVA-induced asthma model in mice. XQL can inhibit mucus hypersecretion and could be a new type of pharmacotherapy.

Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells.

Airway mucus hypersecretion contributes to the morbidity and mortality in patients with chronic inflammatory lung diseases. Reducing mucus production is crucial for improving patients' quality of life. The transcription factor SAM-pointed domain-containing Ets-like factor (SPDEF) plays a critical role in the regulation of mucus production and, therefore, represents a potential therapeutic target. This study aims to reduce lung epithelial mucus production by targeted silencing SPDEF using the novel strategy, epigenetic editing. Zinc fingers and CRISPR/dCas platforms were engineered to target repressors (KRAB, DNA methyltransferases, histone methyltransferases) to the SPDEF promoter. All constructs were able to effectively suppress both SPDEF mRNA and protein expression, which was accompanied by inhibition of downstream mucus-related genes [anterior gradient 2 (AGR2), mucin 5AC (MUC5AC)]. For the histone methyltransferase G9A, and not its mutant or other effectors, the obtained silencing was mitotically stable. These results indicate efficient SPDEF silencing and downregulation of mucus-related gene expression by epigenetic editing, in human lung epithelial cells. This opens avenues for epigenetic editing as a novel therapeutic strategy to induce long-lasting mucus inhibition.

271 - Efficacy of long acting sandostatin on reducing mucus production in patients with ileal neobladder

271 - Efficacy of long acting sandostatin on reducing mucus production in patients with ileal neobladder

Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease

Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease. Bromodomain and extra-terminal domain (BET) chromatin adaptors serve as immunomodulators by directly regulating Th17 responses and Th17-mediated pathology in murine models of autoimmunity and infection. Based on this, we hypothesized that BET proteins may also play an essential role in neutrophil-dominant allergic airway disease. Using a murine model of neutrophil-dominant allergic airway disease, we demonstrate that BET inhibition limits pulmonary inflammation and alters the Th17-related inflammatory milieu in the lungs. In addition, inhibition of BET proteins improved lung function (specifically quasi-static lung compliance and tissue elastance) and reduced mucus production in airways. Overall, these studies show that BET proteins may have a critical role in asthma pathogenesis by altering type 17 inflammation, and thus interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma.

Activating Transcription Factor 3 Is Essential for Cigarette Smoke-Induced Mucin Expression via Interaction with Activator Protein-1

Mucus hypersecretion is an important pathologic feature of chronic obstructive pulmonary disease. Activating transcription factor 3 (ATF3) is an adaptive-response gene that participates in various cellular processes. However, little is known about its role in cigarette smoke (CS)-induced mucus hyperproduction. This study aimed to investigate the role and molecular mechanisms of ATF3 in CS-induced Mucin 5AC (MUC5AC) expression. ATF3 was elevated in lung tissues of mice exposed to CS for 12 weeks. Treatment with CS extract significantly induced ATF3 expression and MUC5AC production in human bronchial epithelial cells, NCI-H292, and mouse tracheal epithelial cells. Interference of ATF3 significantly attenuated CS-induced MUC5AC expression in NCI-H292 and human bronchial epithelial cells. Mouse tracheal epithelial cells isolated from Atf3-/- mice also exhibited less MUC5AC production in response to CS extract treatment. Invivo, the Atf3-/- mice also displayed a significantly reduced mucus production relative to wild-type controls in response to chronic CS exposure. Furthermore, a chromatin immunoprecipitation assay revealed increased ATF3 binding to the MUC5AC promoter after CS treatment, and this transcriptional binding was significantly inhibited by knockdown of JUN, a subunit of activator protein-1. These results demonstrate that ATF3 may be involved in activator protein-1 signaling and transcriptional promotion of CS-induced MUC5AC expression in airway epithelial cells.

Efficacy of Long-Acting Octreotide on Reducing Mucus Production in Patients With Ileal Neobladder

PurposeTo evaluate the efficacy of long-acting-release octreotide (trade name Sandostatin) on decreasing mucus secretion, thus reducing catheter obstruction after radical cystectomy and orthotopic reconstruction. Patients and MethodsIn this double-blind, placebo-controlled study, we treated 73 cases of radical cystectomy between the years 2008 and 2014; 65 were deemed eligible for the study. Cases were randomly divided into 2 groups. Group A (n = 32) received 2 doses of 20 mg intramuscular long-acting-release octreotide 4 weeks before and on the day of surgery, while group B (n = 33) received placebo. Catheter irrigation was only performed when there was an obstruction due to a mucus plug. The need for catheter irrigation and the volume of mucus produced by the neobladder were evaluated and compared between the 2 groups. ResultsThe average number of neobladder irrigations required to treat mucus plugs was 2.3 ± 1.5 in group A and 9.5 ± 4.3 in group B (P < .001) before hospital discharge. This number changed to 2.5 ± 1.5 versus 11.4 ± 2.7 in groups A and B, respectively (P < .001), after discharge from the hospital. The 24-hour mucus production at the end of the first week was 5.4 ± 2.7 mL versus 21.5 ± 5.6 mL in groups A and B, respectively (P < .001). At the end of the third week, this amount changed to 5.5 ± 2.3 mL versus 21.8 ± 5.6 mL in groups A and B, respectively (P < .001). ConclusionTwo injections of long-acting-release octreotide can dramatically reduce mucus production and hence catheter obstruction due to mucus plugs after radical cystectomy and orthotopic reconstruction.

Inducible Bronchus-Associated Lymphoid Tissue (iBALT) attenuates pulmonary Th2 responses

Abstract Inducible bronchus-associated lymphoid tissue (iBALT) is an ectopic lymphoid tissue formed in the lung after pulmonary infection or inflammation. This local lymphoid tissue is structurally similar to conventional secondary lymphoid organs (SLOs), with separated B and T cell areas, specialized stromal cells and lymphoid dendritic cells (DCs). The presence of iBALT is typically associated with pulmonary pathology and advanced lung disease, particularly in patients with chronic obstructive pulmonary disease (COPD), rheumatoid lung disease, pulmonary fibrosis and chronic infections, suggesting that iBALT functions to exacerbate local immune responses and pathology. Here, we tested whether the presence of iBALT affected the pulmonary immune responses to allergens. We induced iBALT formation in neonatal mice by pulmonary administration of lipopolysaccharide (LPS), and when the mice were adults, sensitized and challenged them intranasally with ovalbumin (OVA). We found that mice with iBALT exhibited reduced Th2 responses, reduced eosinophil recruitment, reduced goblet cell hyperplasia and reduced mucus production. The presence of iBALT delayed the accumulation of Th2 cells and eosinophils in the lung following challenge and altered the spatial distribution of T cells in the lung. We also found that the more organized iBALT structure was, the fewer eosinophil infiltrates were observed in house dust mite (HDM)-induced allergic inflammation. Although Th2 cells are generated in mice with iBALT, they are concentrated in iBALT area and more dilute in lung parenchyma. Overall, our studies expanded the field of iBALT from observation of what happens in pulmonary diseases to determining the machinery involved in the responses.

Acidic chitinase primes the protective immune response to gastrointestinal nematodes.

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

English

Anthocleista schweinfurthii is used in the traditional management of gastro-duodenal ulcers; this led us to evaluate the gastro-cytoprotective and healing effects of this plant. Anti-ulcer activity of the stem barks aqueous extract of A. schweinfurthii (EAS) was evaluated using five methods: HCl/ethanol; indomethacin-HCl/ethanol; absolute ethanol; pylorus-ligated (acute gastric lesions); and acetic acid-induced chronic ulcers in rats. The parameters assessed were mucus production, gastric ulcer index, pH, acid concentration and volume of gastric contents. Sucralfate, cimetidine and ranitidine were used as the reference anti-ulcer drugs. In all cases, oral administration of EAS (250 and 500 mg/kg), dose-dependently, prevented gastric lesion formation (p<0.001). Generally, this cytoprotective action was accompanied by significant increases in gastric mucus production. Intraperitoneal indomethacin (30 mg/kg) significantly reduced mucus production but did not reduce the cytoprotective effect. In pylorus ligation, the extract did not reduce acidity and volume of gastric juice compared to controls. All doses of the extract showed a highly significant (p<0.001) reduction of ulceration with a healing rate over 90%. This study indicates that A. schweinfurthii possesses significant anti-ulcer activity and these results are substantiated by the histopathological examination of the ulcerated stomachs. Key words: Gastric, ulcer, cytoprotection, Anthocleista schweinfurthii, Loganiaceae.

Influence of Diclofenac Sodium on Biochemical Indicators of Stomach Mucosa Conditions Against the Background of Excess and Deficiency of Hydrogen Sulfide in Rats

In this article the effect of diclofenac sodium on biochemical parameters of gastric mucosa against the background of deficit and excess of hydrogen sulfide in rats was investigated. It turned out that such NSAIDs increased the process of peroxidation of lipid and protein and caused an imbalance in the system of antioxidant, disturbed the phospholipid spectrum and reduced mucus production of glycosaminoglycans in stomach. Administration of diclofenac sodium against background of H 2S deficit is accompanied by an increasing of range of these changes in metabolic processes in gastric mucosa, while its use with H 2S donor normalizes the course of biochemical processes in gastric mucosa.

Alteration in Pimephales promelas mucus production after exposure to nanosilver or silver nitrate.

The fish gill's ability to produce mucus effectively is a critical part of the stress response and protection against xenobiotic toxicity. Adult fathead minnows were exposed to silver nitrate (0.82 µg/L or 13.2 µg/L), polyvinylpyrrolidone-coated silver nanoparticles (11.1 µg/L or 208 µg/L), and citrate-coated silver nanoparticles (10.1 µg/L or 175 µg/L) for 96 h. Mucus concentrations based on glucose as a surrogate were determined at 0 h, 1 h, 2 h, 3 h, 4 h and 24 h after re-dosing each day. Higher mucus production rates following silver treatment were observed at the beginning as compared to controls and compared to after 3 d of exposure. Control fish produced consistent mucus concentrations throughout the exposure (0.62 mg/L and 0.40 mg/L at 24 h and 96 h, respectively). Following 24 h of exposure, all silver treatment groups produced significantly more mucus than controls. Following 96 h of exposure, mucus concentrations in treatment groups were significantly reduced compared with each respective treatment at 24 h. Reduced mucus production following long-term silver exposure could prevent the gills from removing silver, and thus increase toxicity.

Dry powder formulation of simvastatin

Objectives: This study focuses on the development of a dry powder inhaler (DPI) formulation of simvastatin (SV), and the effects of SV on the respiratory epithelium.Methods: Micronised SV samples were prepared by dry jet-milling. The long-term chemical stability and physicochemical properties of the formulations were characterised in terms of particles size, morphology, thermal and moisture responses. Furthermore, in vitro aerosol depositions were performed. The formulation was evaluated for cell viability and its effect on cilia beat activity, using ciliated nasal epithelial cells in vitro. The formulation transport across an established air interface Calu-3 bronchial epithelial cells and its ability to reduce mucus secretion was also investigated.Results: The particle size of the SV formulation and its aerosol performance were appropriate for inhalation therapy. Moreover, the formulation was found to be non-toxic to pulmonary epithelia cells and cilia beat activity up to a concentration of 10−6 M. Transport studies revealed that SV has the ability to penetrate into airway epithelial cells and is converted into its active SV hydroxy acid metabolite. Single dose of SV DPI also decreased mucus production after 4 days of dosing.Conclusion: This therapy could potentially be used for the local treatment of diseases like chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis given its anti-inflammatory effects and ability to reduce mucus production.

Targeting Mucus Hypersecretion: New Therapeutic Opportunities for COPD?

Airway mucus has a key role in protective innate immune responses, but excessive mucus production and secretion in proximal and in distal airways are associated with disabling symptoms (cough and sputum), lung function decline, exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD). Cellular and molecular mechanisms leading to mucin production and secretion have largely been identified using cultured epithelial cells and animal models. Cigarette smoke and microbial products are potent triggers of mucin production, which involves recognition of specific molecular patterns by cognate receptors and activation of metalloproteases at the epithelial cell surface, leading to epidermal growth factor receptor activation and mucin mRNA and protein synthesis. After mucin synthesis has occurred, mucins are tightly packed into intracytoplasmic granules. Many stimuli induce secretion of mucin granules from epithelial cells, but neutrophil serine proteases are the most potent inducers of mucin secretion. Neutrophils recruited to the airway epithelium also promote mucin production via neutrophil proteases and oxidative stress. Several drugs currently available for the treatment of COPD patients reduced mucus hypersecretion in preclinical models relevant to COPD, but their effects on mucus hypersecretion in humans have not been assessed. Testing the effects of these drugs and of novel molecules designed for reducing mucus production and/or secretion will require performing specifically designed clinical trials. These trials will be necessary to explore the hypothesis that reducing mucus hypersecretion is beneficial in COPD patients.

IL-13-induced airway mucus production is attenuated by MAPK13 inhibition.

Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.

Humanized Mouse Model Used to Monitor MUC Gene Expression in Nasal Polyps and to Preclinically Evaluate the Efficacy of Montelukast in Reducing Mucus Production

To determine whether MUC gene expression could be down-regulated in nasal polyps by the leukotriene receptor antagonist montelukast, we developed a system in which nondisrupted human nasal polyps could be successfully implanted into severely immunocompromised mice, and in which the histopathology of the original nasal polyp tissue could be preserved for long periods. In addition, the histopathologic changes in the human nasal polyps were carefully examined to determine the origin of the submucosal glands (SMGs) that develop in true nasal polyps found in the anterior third of the nose. Small, nondisrupted pieces of human nasal polyp tissues were subcutaneously implanted into NOD-scid IL-2rgamma(null) mice. Xenograft-bearing mice were treated with either montelukast or saline solution. Xenografts at 8 to 12 weeks after implantation were examined histologically, and expression of MUC genes 4, 5AC, and 7 was studied in the polyps before implantation and in the 8-week xenograft. Alzet pumps were inserted into the mice, and montelukast (Singulair) was continuously delivered to determine its effect on goblet cell hyperplasia, mucus production, and the enlargement of nasal polyps over an 8-week period. The xenografts were maintained in a viable and functional state for up to 3 months and retained a histopathology similar to that of the original tissue, but with a noticeable increase in goblet cell hyperplasia and marked mucus accumulation in the SMGs. MUC4 and MUC5AC were significantly increased in the xenograft 8 weeks after implantation, but MUC7 was significantly decreased compared to the preimplantation polyps. Inasmuch as MUC7 is found exclusively in serous glands, the findings suggest that serous glands are not found in polyps in the anterior third of the nose. The histopathologic findings confirm the original findings of Tos et al suggesting that the SMGs are derived from pinching-off of the epithelium of the enlarging polyp following inflammatory changes. These SMGs have the same epithelium as surface epithelium and consist of multiple goblet cells that secrete periodic acid Schiff stain-positive mucin into the interior of the SMGs. A progressive increase in the volume of the xenografts was observed, with little or no evidence of mouse cell infiltration into the human leukocyte antigen-positive human tissue. An average twofold increase in polyp volume was found 2 months after engraftment. Montelukast did not decrease the growth of the xenograft in the 8-week NOD-scid mice, nor did it affect MUC gene expression. The use of innate and adaptive immunodeficient NOD-scid mice homozygous for targeted mutations in the IL-2 gamma-chain locus NOD-scid IL-2r gamma(null) for establishing engraftment of nondisrupted pieces of human nasal polyp tissues represents a significant advancement in studying chronic inflammation over a long period of time. In the present study, we utilized this humanized mouse model to confirm our prediction that MUC genes 4 and 5AC are highly expressed and significantly increased over those of preimplanted polyps. The overexpression of these 2 MUC genes correlates with both the goblet cell hyperplasia and the excessive mucus production that are found in nasal polyp xenografts. MUC7, which is primarily associated with the submucosa, as opposed to MUC4 and MUC5AC, which are primarily expressed in the epithelium, was significantly decreased in the nasal polyp xenografts. Montelukast had no significant effect on MUC gene expression in the xenografts. In addition to the MUC gene expression patterns, the histology of the xenografts supports the concept that mucinous glands that are characteristic of true nasal polyps are significantly different from those in the mucosa found in the lateral wall of the nose in patients with chronic sinusitis without nasal polyps. The mucinous glands seen in nasal polyps (which appear to be derived from an invagination of hyperplastic epithelial mucosa containing large numbers of goblet cells) are histologically distinct from the seromucinous glands found in the submucosa of hyperplastic middle turbinates. The data presented here establish a humanized mouse model as a viable approach to study nasal polyp growth, to assess the therapeutic efficacy of various drugs in this chronic inflammatory disease, and to contribute to our understanding of the pathogenesis of this disease.

Intensive Management of Chronic Bronchorrhea in a Tracheostomized Duchenne Patient with Bronchiectasis

Duchenne muscular dystrophy (DMD) is a severe X-linked hereditary neuromuscular disease characterized by progressive muscle degeneration and functional tetraplegia. Advances related to the use of mechanical ventilation and techniques of airway clearance have improved the lifespan of these patients until 30-35 years. In a 27 years old home-ventilated tracheostomized DMD patient affected by bronchiectasis and atelectasis with excessive bronchorrhea (>300ml mucus production/24h), endotracheal suctioning act became so frequent that it severely affected his mental health and that of his family. An intensive programme of airway clearance including ventilation via Intrapulmonary Percussive Ventilation (IPV) and suctioning via mechanical insufflation-exsufflation (MI-E) associated with strong manual chest compression improved mean nocturnal SpO2 from 91 to 95% and reduced mucus production and suctioning rate by 50%. The perceived physical and emotional health (SF-36) increased in the patient and in his family. In the patient, the general mental health score increased from 16 to 48%, the vitality from 10 to 40% and the general health perception from 10 to 35%. In the patient’s father, the social functioning improved from 38 to 63%, the general mental health from 36 to 60% and the vitality from 35 to 60%. In this report, intensive respiratory therapy with IPV in combination with MI-E and chest compression was safe and spectacularly improved the quality of ventilation, the mucus production and the perceived mental health in an adult Duchenne patient with bronchorrhea.

IL-17–Induced Pulmonary Pathogenesis during Respiratory Viral Infection and Exacerbation of Allergic Disease

Severe respiratory syncytial virus (RSV) infections are characterized by airway epithelial cell damage, mucus hypersecretion, and Th2 cytokine production. Less is known about the role of IL-17. We observed increased IL-6 and IL-17 levels in tracheal aspirate samples from severely ill infants with RSV infection. In a mouse model of RSV infection, time-dependent increases in pulmonary IL-6, IL-23, and IL-17 expression were observed. Neutralization of IL-17 during infection and observations from IL-17(-/-) knockout mice resulted in significant inhibition of mucus production during RSV infection. RSV-infected animals treated with anti-IL-17 had reduced inflammation and decreased viral load, compared with control antibody-treated mice. Blocking IL-17 during infection resulted in significantly increased RSV-specific CD8 T cells. Factors associated with CD8 cytotoxic T lymphocytes, T-bet, IFN-γ, eomesodermin, and granzyme B were significantly up-regulated after IL-17 blockade. Additionally, in vitro analyses suggest that IL-17 directly inhibits T-bet, eomesodermin, and IFN-γ in CD8 T cells. The role of IL-17 was also investigated in RSV-induced exacerbation of allergic airway responses, in which neutralization of IL-17 led to a significant decrease in the exacerbated disease, including reduced mucus production and Th2 cytokines, with decreased viral proteins. Taken together, our data demonstrate that IL-17 plays a pathogenic role during RSV infections.

TNFRSF25 mediated in vivo expansion of regulatory T-cells reduces immunopathology in a chronic model of allergic lung inflammation (55.4)

Abstract TNF receptor super family member 25 (TNFR25, DR3) signaling by agonistic antibody (4C12) has been shown to effectively expand CD4+FoxP3+ regulatory T-cells (Treg) in vivo, and prevent acute allergic lung inflammation, a model for asthma. Here we investigate if Treg expansion by TNFR25 stimulation can reduce lung immunopathology associated with chronic allergic lung inflammation. After antigen priming (Ovalbumin/ALUM) and three weeks of antigen aerosol exposure (Ovalbumin in Saline), TNFR25 agonistic antibody given during an aerosol-free period is able to expand Tregs in the peripheral blood and in the lungs as previously reported. After two additional weeks of antigen aerosol exposure, and at a time when TNFR25-expanded Tregs have almost contracted to baseline levels, 4C12 treated animals remained protected from chronic lung immunopathology. Specifically, TNFR25 agonistic antibody treated mice, as compared to IgG treated controls, showed reduced eosinophils in the bronchoalveolar lavage fluid, reduced expression of Th2 cytokines (IL-4, IL-5, IL-13), CCL11 (eotaxin-1), and TNF-a, and reduced mucus production in the bronchial epithelium. These results indicate that TNFR25 mediated expansion of Tregs after established pulmonary inflammation, is able to generate a sustained suppression of chronic lung immunopathology, which may be mediated by antigen-specific Tregs.

S100A8 Modulates Mast Cell Function and Suppresses Eosinophil Migration in Acute Asthma

S100A8 is implicated in the pathogenesis of inflammatory diseases. S100A8 is upregulated in macrophages by Toll-like receptors (TLR)-3, 4, and 9 agonists in an IL-10-dependent manner, and by corticosteroids in vitro and in vivo, and scavenges oxidants generated by activated phagocytes. Because if its elevated expression in various lung disorders, we asked whether S100A8 was protective in allergic inflammation. S100A8, but not Cys(41)-Ala S100A8, in which the single reactive Cys residue was replaced by Ala, reduced mast cell (MC) degranulation and production of particular cytokines (IL-6, IL-4, and granulocyte macrophage colony-stimulating factor) in response to IgE-crosslinking in vitro, likely by inhibiting intracellular reactive oxygen species production, thereby reducing downstream linker for activation of T cells and extracellular signal regulated kinase/mitogen-activated protein kinase phosphorylation. In lungs of mice with acute asthma, S100A8, but not Cys(41)-Ala S100A8, reduced MC degranulation, production of eosinophil chemoattractants (IL-5, eotaxin, and monocyte chemoattractant protein-1), and eosinophil infiltration. Suppression of IL-6 and IL-13 could have contributed to reduced mucus production seen in lungs of S100A8-treated mice. IgE production was unaffected. In asthma, there is an imbalance of anti-oxidant systems that are generally protective. Our results strongly support a protective role for S100A8 in allergic inflammation by modulating MC activation and eosinophil recruitment, and by scavenging oxidants generated by activated leukocytes, in processes reliant on its thiol-scavenging capacity.

Heat shock protein 90 inhibitors reduce airway inflammation in a mouse model of allergic asthma.

Narrowing of the airways, the cardinal feature of asthma, is frequently a result of airway inflammation that produces mucous hyper‐secretion and airway smooth muscle proliferation and migration, leading to airway remodeling. Heat shock protein 90 (hsp90) inhibitors are a new class of chemotherapeutics that have also been reported to possess strong anti‐inflammatory activity. Thus, the present study was designed to test the hypothesis that hsp90 inhibitors may ameliorate the airway inflammation associated with allergic asthma. Female BALB/c mice were subjected to a standard 25‐day regimen of saline (control mice) or ovalbumin (OVA) sensitization (asthmatic mice). During the last week of OVA treatment, mice also received a daily dose of either vehicle or of the hsp90 inhibitor, 17‐AAG (5mg/kg/day, intranasally). On day 26, mice were anesthetized and bronchoalveolar lavage (BAL) was performed. Asthmatic mice exhibited pronounced leukocytosis in the BAL fluid (BALF) compared to controls. This increase in BALF leukocytes was prevented in asthmatic mice treated with 17‐AAG. BALF cell differential analysis showed that, compared to vehicle‐treated asthmatics, a significant decrease in the number of neutrophils occurred in 17‐AAG‐treated asthmatic mice. Similarly, histological examination of lungs fixed by tracheal instillation, demonstrated less inflammation, less cell infiltration and reduced mucus production in the airways of asthmatic animals treated with 17‐AAG, as compared to vehicle‐treated asthmatic mice. These data suggest that hsp90 inhibitors may be useful in the management of allergic asthma.