Bronchitis In Humans Research Articles

Broncho-Vaxom bacterial lysate prevents asthma via acetate enhancement in mouse model.

Broncho-Vaxom (BV) is known to attenuate allergic airway inflammation and chronic bronchitis in humans, but the underlying mechanism of this gut-mediated immunity remains unclear. This study investigated the effects of an oral BV on gut and systemic short-chain fatty acids (SCFAs) and immune responses. Oral BV was administered daily for 15 days prior to commencing the study in an asthma mouse model. Asthma was induced by ovalbumin (OVA) sensitization followed by a challenge with 1% OVA by inhalation. Asthmatic phenotypes, gut- and systemic- immune responses, and SCFAs in the cecum and blood were then investigated. Airway hyperresponsiveness, total immunoglobulin E production, and pulmonary inflammation were all significantly suppressed by BV. The interleukin-13 level was also suppressed, whereas TGF-β expression was increased, in the lungs of the BV-treated mice. The regulatory T (Treg) cell numbers were increased in the small intestine, and the acetate level was increased in the cecum and serum after BV treatment. The levels of acetate in the cecum and serum were negatively correlated with airway hyperresponsiveness and with the eosinophil numbers in the BAL fluid of the OVA-induced mice. There was a positive correlation between the acetate levels in the feces and serum and the lung expression of TGF-β in the asthma mice. Oral BV administration appears to prevent allergic inflammation by enhancing Treg cell proliferation and acetate production in an asthmatic mouse model.

Airway remodeling in ferrets with cigarette smoke-induced COPD using µCT imaging.

Structural changes to airway morphology, such as increased bronchial wall thickness (BWT) and airway wall area, are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. Our objective was to develop a microcomputed tomography (µCT) method for evaluating structural changes to the airways in ferrets and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 mo. µCT was conducted in vivo at 6 mo; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT-to-LD ratio (BWT/LD) were conducted and confirmed by a semiautomated algorithm. The square root of bronchial wall area (√WA) versus luminal perimeter was determined on an individual ferret basis. Smoke-exposed ferrets reproducibly demonstrated 34% increased BWT (P < 0.001) along with increased LD and BWT/LD versus air controls. Regression indicated that the effect of smoking on BWT persisted despite controlling for covariates. Semiautomated measurements replicated findings. √WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke-exposed ferrets (P = 0.015). Increased BWT and Pi4 developed steadily over time. µCT-based airway measurements in ferrets are feasible and reproducible. Smoke-exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

Molecular Characterization of a Dirofilaria immitis Cysteine Protease Inhibitor (Cystatin) and Its Possible Role in Filarial Immune Evasion.

Infection with canine heartworm (Dirofilaria immitis), spread via mosquito vectors, causes coughing, asthma, pneumonia, and bronchitis in humans and other animals. The disease is especially severe and often fatal in dogs and represents a serious threat to public health worldwide. Cysteine protease inhibitors (CPIs), also known as cystatins, are major immunomodulators of the host immune response during nematode infections. Herein, we cloned and expressed the cystatin Di-CPI from D. immitis. Sequence analysis revealed two specific cystatin-like domains, a Q-x-V-x-G motif, and a SND motif. Phylogenetic analysis indicates that Di-CPI is a member of the second subgroup of nematode type II cystatins. Probing of D. immitis total proteins with anti-rDi-CPI polyclonal antibody revealed a weak signal, and immunofluorescence-based histochemical analysis showed that native Di-CPI is mainly localized in the cuticle of male and female worms and the gut of male worms. Treatment of canine peripheral blood mononuclear cells (PMBCs) with recombinant Di-CPI induced a Th2-type immune response characterized by high expression of the anti-inflammatory factor interleukin-10. Proliferation assays showed that Di-CPI inhibits the proliferation of canine PMBCs by 15%. Together, the results indicate that Di-CPI might be related to cellular hyporesponsiveness in dirofilariasis and may help D. immitis to evade the host immune system.

Erdosteine therapy for renal failure: current perspectives.

Dear Editor, I read the recently published paper of Ebru Uz et al. (1), in the Nephro-Urology Monthly which focused on the renoprotective effects of erdosteine when it is used for cyclosporine-A (CsA) induced chronic nephrotoxicity. Erdosteine belongs to the class of mucolytics which is used for the treatment of wet cough and chronic obstructive pulmonary disease (COPD). It has been reported that erdosteine possesses multiple mechanisms to protect against hepatic, renal, retinal and cardiotoxicity (2, 3). Erdosteine is a prodrug and metabolite I is the active metabolite of erdosteine owing to its free thiol group. It modifies the clinical outcome by improving the symptoms and reducing the progress of the disease. Pharmacokinetics of erdosteine results in rapid absorption after oral administration; distribution with protein binding is 64.5%; first pass metabolism to form an active metabolite i.e., N-thiodiglycolyl-homocysteine t1/2 4.6 hour in rats; excretion through urine as metabolites, elimination half-life approximately 1.46 hr (erdosteine), and about 1.62 hr (metabolite). Common adverse reactions/side effects are epigastralgia, nausea, vomiting, diarrhea, spasmodic colitis, taste alteration, urticaria, eczema, erythema and headaches (4). Contraindications are, caution to be used during pregnancy and lactation. Erdosteine contains two sulfhydryl groups and it is reported that in the pharmacodynamics it breaks the disulphide bonds, which hold the glycoprotein fibers of mucus together. Furthermore, it makes the secretions and mucous more fluid which enhances elimination (5). CsA is an immunosuppressant drug widely used in post-allogeneic organ transplants to reduce the activity of the immune system, and therefore it lessens the risk of organ rejection. CsA, was initially isolated from the fungus Tolypocladium inflatum and extracted from a soil sample, this was obtained by Sandoz scientists at Hardangervidda, Norway in 1969 (6). However, CsA is a very lipophilic agent, and this facilitates attachment to cellular membranes leading to lipid degradation and peroxidation with further release of free radicals and oxidative stress which may result in CsA-resistance and nephrotic syndrome (1, 7). I agree with Ebru Uz et al. that erdosteine may protect renal tissue by alteration of CsA induced rising oxidative stress markers i.e., glutathione peroxidase, catalase, malondialdehyde and nitric oxide levels along with histopathological changes (1). Furthermore, erdosteine may improve several toxic drug side effects such as those found in CsA, gentamicin, paracetamol, vancomycin and radiocontrast induced renal dysfunction (8, 9). On the other hand, it could also have a positive impact on other anti-oxidant enzymes i.e., xanthine oxidase and myeloperoxidase, as well as renal functional markers i.e., blood urea nitrogen, serum creatinine, uric acid, total protein, and albumin levels (2, 9). So it seems that the administration of erdosteine might be useful for the management of renal dysfunction. Erdosteine is generally well tolerated in human studies for the management of wet cough and COPD. However, mucolytics such as erdosteine are cautioned in patients with a history of peptic ulcer. As a prodrug, erdosteine may be less likely to disrupt the gastric mucosal barrier but the use of erdosteine is also contraindicated in patients with an active peptic ulcer (4). Hence, there still remains a number of big questions to explore further; (i) possible different routes of administrating erdosteine for the management of renal failure is questionable due to an alteration in the variety of metabolic enzymes, (ii) the potential molecular mechanism of erdosteine for the beneficial effects on renal toxicity still remains unexplored, and (iii) it is clinically approved for wet cough and chronic bronchitis in humans, but relevant clinical reports for the management of renal failure still needs to be explored in human subjects. In addition, until more robust data is available the use of erdosteine cannot be recommended (10). So it is difficult to suggest the administration of erdosteine for renal failure patients because the signs and symptoms of erdosteine overlap with the health status of human subjects. However, extensive clinical studies with different doses of erdosteine are warranted in order to clarify this issue.

Quantification of mucin gene expression in tracheobronchial epithelium of healthy dogs and dogs with chronic bronchitis

To develop a real-time PCR assay for the quantification of mucin gene expression in tracheobronchial brushing specimens from dogs and compare mucin gene expression in specimens from dogs with naturally occurring chronic bronchitis with that in specimens from healthy dogs. 7 healthy dogs and 5 dogs with chronic bronchitis. Primers that were designed to span the predicted intron-exon boundaries of a canine MUC5AC-like gene were used to develop a real-time PCR assay for quantification of expression of that gene. Total mRNA was isolated from tracheobronchial brushing specimens obtained from dogs with and without bronchitis during anesthesia; MUC5AC-like gene expression in those samples was quantified by use of the real-time PCR assay. The PCR assay was sensitive and specific for the target sequence, the predicted amino acid sequence of which had greatest homology with human, porcine, and rat MUC5AC. The assay was able to quantify the target over a wide dynamic range. Dogs with chronic bronchitis had a 3.0-fold increase in the quantity of MUC5AC-like mRNA, compared with healthy dogs. The ability to measure mucin gene expression from tracheobronchial brushing specimens collected from client-owned dogs during routine bronchoscopy should prove to be a useful tool for the study of bronchitis in dogs and expand the usefulness of airway inflammation in dogs as a model for bronchitis in humans.

Animal models of asthma and chronic bronchitis.

Human asthma is characterized by three critical phenotypic traits: intermittent reversible airway obstruction, airway hyperresponsiveness and airway inflammation. In animal models of asthma, airway hyperresponsiveness is an important feature. This trait is characterized by an exaggerated bronchoconstrictor response that would have little physiological consequence in an otherwise unaffected or normal individual. In this article we explore two distinct facets of airway responsiveness. The first is the genetic basis for variations in airway responsiveness that occur in mice in the absence of any specific environmental manipulation. We demonstrate that standard genetic approaches can be successfully applied to the identification of regions of the mouse genome linked to the expression of airway hyperresponsiveness. The second topic addressed in this review is the change in airway responsiveness induced in rats by repeated exposure to sulphur dioxide gas. With daily exposure to high concentrations of sulphur dioxide gas, there is chronic injury and repair of epithelial cells. Over time, rats develop mucous hypersecretion, airway inflammation, increased airway resistance and airway hyperresponsiveness. This model has provided useful information on the mechanisms underlying the pathophysiological events that typify the chronic bronchitis in humans.

Increased airway responsiveness to inhaled methacholine in a rat model of chronic bronchitis.

Chronic exposure of rats to high concentrations of SO2 gas causes pathologic changes in airway similar to those seen in human chronic bronchitis. The purpose of this study was to examine the pulmonary mechanical correlates of these changes and to quantify the extent of mucous hypersecretion by measuring changes in mucous glycoproteins. Female Sprague-Dawley rats were exposed to 250 ppm SO2 gas, 5 h/d, 5 d/wk, for a period of 4 wk. Control rats were exposed to air only. On the day after the last SO2 exposure, rats were anesthetized, instrumented for the measurement of pulmonary resistance (RL) and dynamic compliance (Cdyn), and ventilated. Chronic SO2 exposure caused a small but significant increase in RL and decrease in Cdyn. Airway responsiveness to inhaled aerosolized methacholine was increased in SO2-exposed rats, as indicated by approximately 6.6- and 4.6-fold decreases respectively, in the doses of inhaled methacholine required to double RL or decrease Cdyn to 50% of baseline. SO2 exposure had no effect on the contractile response of the trachea measured in vitro. Tracheae and lungs from SO2-exposed animals exhibited 140 and 535% increases in measured neutral mucous glycoproteins, respectively, and 33 and 37% increases in acid glycoproteins. Our results indicate that this animal model of chronic bronchitis mimics the mucous hypersecretion, airway obstruction, and increased airway responsiveness observed in human bronchitis and may allow us to begin to probe their mechanistic basis.

Sulfur dioxide induced bronchitis in rats.

The effects of subchronic inhalation of 300 ppm and 400 ppm SO2 gas on airway mucus production and the distribution and density of respiratory tract goblet cells was examined in rats. The changes in the goblet cell population and mucus hypersecretion were examined over a 6-week period, with interim sacrifices at 3 and 4 weeks. Subacute exposure to 300 ppm SO2 produced a bronchitic syndrome in rats similar to that observed in human bronchitis. Inhalation of 300 ppm SO2 produced predominantly a large airway mucus cell hyperplasia with practically no loss in cellularity, or ablation as was observed with 400 ppm. In addition, the inhalation of both 300 ppm and 440 ppm SO2 induced a hypersecretion of mucus resulting in mucus accumulation throughout the respiratory tract.

Physiological and histological alterations in the bronchial mucociliary clearance system of rabbits following intermittent oral or nasal inhalation of sulfuric acid mist.

Rabbits were exposed to submicometer sulfuric acid mist (H2SO4) for 1 h/d, 5 d/w for 4 wk, during which time mucociliary clearance was monitored by external in vivo measurements of tagged tracer aerosol retention. One group was exposed orally to 250 micrograms/m3, another to the same concentration via the nose, and a third to 500 micrograms/m3 also via nasal breathing. Clearance was accelerated on specific individual days during the course of the acid exposures, especially at 500 micrograms/m3. In all series, clearance was significantly faster, compared to preexposure controls, during a 2-wk follow-up period after acid exposures had ceased. At the end of this period, the rabbits were sacrificed, and histological sections were obtained from the tracheobronchial tree. Significantly increased epithelial thickness of small conducting airways, compared to sham exposure controls, occurred in rabbits exposed orally at 250 micrograms/m3 or nasally at 500 micrograms/m3, and additionally the lumen of the smallest airways of the former group was narrower than control. The number of airways containing epithelial secretory cells was also significantly greater in these acid exposure groups compared to sham controls. The only change in the rabbits exposed nasally at 250 micrograms/m3 was a significant increase in the number of airways with epithelial secretory cells in the smallest airway classification. The histological alterations provide a basis for observed changes in clearance, and are similar to those found in chronic bronchitis in humans and experimental animals. Differences in site and degree of histological response and degree of physiological change between the two groups exposed to identical acid concentrations appear to have been due to differences in exposure mode, with resultant effects on breathing pattern, aerosol size distribution, and concentration penetrating beyond the upper respiratory tract to specific lung sites.

EFFECTS OF SULPHURIC ACID AEROSOLS ON RESPIRATORY TRACT AIRWAYS

Abstract Inhalation exposure studies in humans and donkeys in this laboratory have indicated that the physiological effects produced by 0.5 μm H 2 SO 4 droplets at concentrations well below current TLVs may contribute to the pathogenesis of chronic bronchitis. This paper demonstrates that the effects of inhaled submicrometer H 2 SO 4 on the mucociliary bronchial clearance of γ-tagged Fe 2 O 3 particles are essentially the same as those produced by whole fresh cigarette smoke in terms of: (i) transient accelerations of clearance in low dose exposures (100 μg m -3 H 2 SO 4 for 1 h and 2-7 cigarettes); (ii) transient slowing of clearance following high dose exposures (1 mg m -3 H 2 SO 4 for 1 h and ≥ 15 cigarettes); and (iii) alterations in clearance rates persisting for several months following multiple exposures (>6 1-h exposures at 200-1000 μg m -3 H 2 SO 4 , 6 months of daily exposure to 100 μg m -3 H 2 SO 4 for 1 h/day, and 4–8 months of 30 cigarettes, 3 times/week). These similarities, together with the well established role of cigarette smoking in the causation of chronic bronchitis in humans, establishes a need for further close examination of the role of H 2 SO 4 inhalations in the etiology of chronic bronchitis.