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Objectives Saccharin test (ST) is a convenient method to assess the efficiency of mucociliary clearance, the primary defense mechanism of the upper airways’ tract. The study objectives are to: (1) substantiate its short- (3 days) and long-term (30 days) repeatability; (2) assess its tolerability; (3) conduct a systematic literature review and to compare our results with the existing evidence.Methods Twenty-nine healthy subjects were enrolled in an observational prospective study to perform an ST on three separate visits (at baseline; at follow-up visits at day 3 and at day 30). Transit times were recorded and self-reported nasal and general symptoms noted. A systematic review of the literature was conducted to compare our results with the existing literature.Results The mean values (±SD) of ST transit time (STTT) were 7.085 (±2.19), 7.788 (±2.11), and 7.790 (±2.06) minutes at baseline, day 3, and day 30, respectively. Significant linear regression analysis was observed between day 3 and baseline (r= .193; P= .019) and day 30 and baseline (r= .182 P= .024). Significant agreement for the intrasession repeatability was observed with an ICC = .354 (P= .001). Outcomes’ comparisons between baseline vs day 3 (P= .197) and baseline vs day 30 (P= .173) were not statistically significant. ST was well tolerated. Concordance with existing literature’s data and high level of STTT repeatability were confirmed by the qualitative analysis.Conclusion STTT reproducibility was good both in the short- and long-term. ST tolerability was very good. Our study data are consistent with the existing literature, indicating ST as a sound methodology for detection of early respiratory health changes and for specific regulatory application in respiratory research.

Vaping by adolescents and young adults is a legitimate concern as there is a risk that some may start smoking and that electronic cigarette (EC) use may have adverse effects in the developing lungs of adolescents. This commentary provides updated information on vaping patterns among adolescents and young adults in the United States, as well as the impact of EC usage on respiratory health.

Globally, around half the adult asthma population are current or former cigarette smokers. Cigarette smoking and asthma interact to induce an “asthma-smoking phenotype(s),” which has important implications for diagnosis, pathogenic mechanisms, and management. The lack of progress in understanding the effects of smoking on adults with asthma is due in part to their exclusion from most investigative studies and large clinical trials. In this review, we summarize the adverse clinical outcomes associated with cigarette smoking in asthma, highlight challenges in diagnosing asthma among cigarette smokers with chronic respiratory symptoms, particularly in older individuals with a long-standing smoking history, and review pathogenic mechanisms involving smoking- and asthma-related airway inflammation, tissue remodeling, corticosteroid insensitivity, and low-grade systemic inflammation. We discuss the key components of management including the importance of smoking cessation strategies, evidence for the effectiveness of the Global Initiative for Asthma recommendations on treatment in cigarette smokers, and the role of treatable traits such as type 2 eosinophilic airway inflammation. Lastly, we provide an algorithm to aid clinicians to manage current and former smokers with asthma. In the future, controlled and pragmatic trials in real-world populations should include cigarette smokers with asthma to provide an evidence base for treatment recommendations.

Background: Tobacco smoking exacerbates diabetes-related complications; its prevalence is notwithstanding substantial. Persons with diabetes face a number of barriers and challenges to quitting such as multiple lifestyle restrictions; tailored interventions are required for smoking cessation.Objective: To identify research on behavioral interventions for smoking cessation in diabetes.Methods: Studies had to be randomized controlled trials, quasiexperimental or systematic reviews. The behavioral interventions included were: the 5As, Cognitive-Behavioral Therapy, Motivational Interviewing, Contingency Management, Health Coaching and Counselling, as compared to standard care. The outcomes were self-reported and/or biochemically verified smoking cessation. CINAHL Complete, MEDLINE Complete, the Cochrane databases of systematic reviews and randomized controlled trials, PsychInfo and PubMed Central were searched until July, 2023. Keywords used included diabetes, smoking cessation and each of the behavioral interventions included.Results: 1615 papers were identified. Three studies on the 5As/brief advice, 4 on Motivational Intervention and 1 on counseling were retained. The results on the 5As and Motivational Interviewing were conflicting. More intensive interventions appear to be more successful in achieving smoking cessation in smokers with diabetes.Conclusions: Future research should focus on the continued development and evaluation of structured smoking cessation interventions based on the 5As, Motivational interviewing and Cognitive Behavioral Therapy.

Background: The key ingredients of e-cigarettes liquid are commonly propane-1,2-diol (also called propylene glycol) and propane-1,2,3-triol (vegetal glycerol) and their antimicrobial effects are already established. The nicotine and flavors which are often present in e-liquids can interfere with the growth of some microorganisms. Objective: The effect of combining these elements in e-liquids is unknown. The aim of the study was to investigate the possible effects of these liquids on bacterial growth in the presence or absence of nicotine and flavors. Methods: Susceptibilities of pathogenic strains (Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Enterococcus faecalis and Sarcina lutea) were studied by means of a multidisciplinary approach. Cell viability and antioxidant assays were also evaluated. Results: All e-liquids investigated showed antibacterial activity against at least one pathogenic strain. Higher activity was correlated to the presence of flavors and nicotine. Discussion: In most cases, the value of minimal bactericidal concentration is equal to the value of minimal inhibitory concentration showing that these substances have a bactericidal effect. This effect was observed in concentrations up to 6.25% v/v. Antioxidant activity was also correlated to the presence of flavors. Over time, the viability assay in human epithelial lung A549 cells showed a dose-dependent inhibition of cell growth. Conclusion: Our results have shown that flavors considerably enhance the antibacterial activity of propane-1,2-diol and propane-1,2,3-triol. This study provides important evidence that should be taken into consideration in further investigative approaches, to clarify the different sensitivity of the various bacterial species to e-liquids, including the respiratory microbiota, to highlight the possible role of flavors and nicotine.

Objectives:To provide an in-depth analysis of noninvasive methods for the early diagnosis of oral premalignant lesions, focusing on novel biomarkers and optical technologies, and to discuss their potential in improving the prognosis of patients with oral oncological diseases. Methods:This state-of-the-art review examines various noninvasive diagnostic techniques, including the utilization of salivary microRNAs and optical technologies such as Raman spectroscopy, elastic scattering spectroscopy, diffuse reflectance spectroscopy, narrow-band imaging, autofluorescence imaging, toluidine blue staining, and microendoscopy. Results:Several noninvasive techniques have shown varying degrees of effectiveness in detecting oral cancer. Autofluorescence imaging exhibited sensitivities up to 100% but had variable specificity. toluidine blue staining reported sensitivity between 77% and 100% for high-risk lesions or cancer, with specificity around 45% to 67%. Spectroscopy techniques achieved 72% to 100% sensitivities and specificities of 75% to 98%. Microendoscopy presented a sensitivity of 84% to 95% and a specificity of 91% to 95%. Conclusion:The review highlights the strengths and limitations of each noninvasive diagnostic method and their recent advancements. Although promising results have been demonstrated, there is a need for further development of reliable strategies for early detection and intervention in oral oncology.

ABSTRACTIntroduction: Asthma is considered one of the most common chronic conditions globally, characterized by variable airflow obstruction and symptoms. Severe asthma is diagnosed when asthma control requires high-intensity therapy or continues to remain uncontrolled despite treatment. Eosinophilic inflammation is known to be perpetuated by the activity of IL-5 in a proportion of severe asthma subjects, and targeting IL-5 may offer a therapeutic option.Areas covered: In this review, we discuss the role and pathogenesis of IL-5 and eosinophils in asthma and rationale of antagonizing IL-5 in severe eosinophilic asthma. Mepolizumab is the first of three anti-IL-5 biologics licensed in 2015 for use in this subgroup of patients. We discuss clinical and real-life studies leading up to its approval and post-marketing outcomes in terms of efficacy and safety to-date, as well as its pros and cons.Expert opinion: IL-5 antagonism has paved the way for an additional personalized therapeutic opportunity for use in severe asthma with eosinophilic inflammation, though there is limited evidence on the long-term implications of suppressing/depleting eosinophils and the duration for which they should be administered.Trial registration:ClinicalTrials.gov identifier: NCT02555371.Trial registration:ClinicalTrials.gov identifier: NCT01290887.Trial registration:ClinicalTrials.gov identifier: NCT02452190.

ABSTRACTIntroduction:Primary Sjögren’s (pSS) syndrome is a chronic, autoimmune, and systemic disease characterized by xerostomia, xerophthalmia, muscle pain and fatigue. The disease may be complicated by a systemic involvement, such as a pulmonary fibrosis or the development of lymphoma which severely worsens the prognosis. Actually, there are no recommendations for the management of pSS. However, recent advances in the understanding of its pathogenesis have uncovered some pathways that have potential as therapeutic targets.Areas covered:In this review, the authors present the biologic drugs potentially valuable to the treatment of pSS in light of its physiopathology with a ‘bird’s eye’ view of future prospects. The authors took into account relevant studies published from 2004 to 2016.Expert opinion:Biological treatment in pSS is a promising opportunity to potentially control disease activity and prevent its complication. Currently, inhibition of B-cell and IL-17 pathways seem to be the most promising avenues. New achievements in the knowledge of pSS pathophysiology are necessary in order to try to simultaneously predict the predominant pathogenic pathway, the kind of patients at major risk to develop a more severe disease, and the appropriate biological therapy to use.

To provide an evidence-based review of common safety concerns and emerging potential benefits deriving from the regular use of electronic cigarettes (ECs) and thus improve counseling between physicians and their patients with asthma and allergy using or intending to use ECs.

The respiratory system is a primary target of the harmful effects of key air pollutants of health concern. Several air pollutants have been implicated including particulate matter (PM), ozone (O3), nitrogen dioxide (NO2) polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs). It is well known that episodes of exposure to high concentrations of outdoor air pollutants can cause acute respiratory exacerbations. However, there is now increasing evidence suggesting that significant exposure to outdoor air pollutants may be also associated with development of lung cancer and with incident cases of chronic obstructive pulmonary disease (COPD) and respiratory allergies. Here we provide a critical appraisal of the impact of air pollution on respiratory diseases and discuss strategies for preventing excessive exposure to harmful air pollutants. However, the evidence that significant exposure to air pollutants is causing COPD, lung cancer or respiratory allergies is not conclusive and therefore regulators must be aware that execution of clean air policies may not be that cost-effective and may lead to unintended consequences. Addressing the lung health effects of air pollution must be considered work in progress.

Autologous fat tissue grafting (AFTG) has been successfully used in the treatment of different sclerotic conditions, including localized scleroderma. Patients with advanced systemic sclerosis (SSc)-related perioral thickening and mouth opening limitation are candidates for this therapeutic approach. AFTG of the lips was performed to improve mouth opening in patients with SSc. We enrolled in the study 20 female patients with diffuse SSc (median age 35 ± 15 years and 11 ± 10 years of disease duration). Two-milliliter fractions of autologous fat drawn from trochanteric or periumbilical areas were injected in eight different sites around the mouth. Baseline and after-treatment mouth opening changes were assessed by measuring interincisal distance and oral perimeter, while skin hardness was tested by digital durometer. Pre- and posttreatment modifications of microvascular architecture were assessed by counting capillaries in the inferior lip videocapillaroscopy (VC) images and by scoring the microvascular density (MVD) in anti-CD34/CD31 immunohistochemical (IH) stained perioral skin biopsy sections. Similarly, histological sections were examined to evaluate dermoepidermic junction (DEJ) modifications. Three months after treatment, both the interincisal distance and oral perimeter significantly increased (p< 0.001). At the same time, a significant skin neovascularization became evident, both considering the VC images (p< 0.001) and MVD scores in IH sections (p< 0.0001). Finally, some skin histological aspects also improved, as shown by the significant changes in DEJ flattening scores (p< 0.0001). The present study suggests that, in patients with SSc, AFTG can improve mouth opening and function, induce a neovascularization, and partially restore the skin structure.

Electronic cigarettes are a recent development in tobacco harm reduction. They are marketed as less harmful alternatives to smoking. Awareness and use of these devices has grown exponentially in recent years, with millions of people currently using them. This systematic review appraises existing laboratory and clinical research on the potential risks from electronic cigarette use, compared with the well-established devastating effects of smoking tobacco cigarettes. Currently available evidence indicates that electronic cigarettes are by far a less harmful alternative to smoking and significant health benefits are expected in smokers who switch from tobacco to electronic cigarettes. Research will help make electronic cigarettes more effective as smoking substitutes and will better define and further reduce residual risks from use to as low as possible, by establishing appropriate quality control and standards.

A growing body of scientific studies show that e-cigarettes may serve as an acceptable substitute for smoking tobacco cigarettes, thereby reducing or eliminating exposure to harmful elements in smoke. The success of e-cigarettes is such that sales of these products are rapidly gaining on traditional cigarettes. The rapidly evolving phenomenon is raising concerns for the health community, pharmaceutical industry, health regulators and state governments. Obviously, these products need to be adequately regulated, primarily to protect users. Depending on the form and intended scope, certain regulatory decisions may have diverse unintended consequences on public health and may face many different challenges. Ideally, before any regulations are enacted, the regulatory body will require sufficient scientific research to verify that a problem does exist, quantify the problem, explore all potential solutions including making no change at all, determine the possible consequences of each, and then select the solution that is best for public health. Here we present an overview on the existing and deeming regulatory decisions for electronic cigarettes. We challenge them, based on the mounting scientific evidence with the ultimate goal of proposing appropriate recommendations while minimizing potential unintended consequences of ill-informed regulation.

Introduction:Adenosine receptors (ARs) and their differential pattern of expression modulate a series of pleiotropic activities that are known to contribute to the control of inflammation, remodeling, and tissue repair. Consequently, pharmacological manipulation of adenosine signaling pathway is of great interest and is currently exploited as a therapeutic target for a number of respiratory diseases with several molecules with agonist and antagonist activities against known ARs being developed for the treatment of different conditions of the respiratory system.Areas covered:Herein, we will review the rational basis leading to the development of novel therapies for asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cystic fibrosis. Their most recent clinical development will be also discussed.Expert opinion:Advances in our understanding of the pathogenetic role of adenosine in respiratory diseases may be soon translated into effective treatment options. In consideration of the complex interplay driven by the different pattern of receptor distribution and/or affinity of the four known AR subtypes in specific cell types at different stages of the disease, it is likely that combination of selective antagonist/agonists for different AR subtypes will be required to obtain reasonable clinical efficacy. Alternatively, controlling the factors involved in driving adenosine concentrations in the tissue may be also of great significance.

Introduction:Omalizumabis a recombinant DNA-derived humanized IgG1 monoclonal antibody that selectively binds to free and membrane-bound immunoglobulin E (IgE) antibodies. Omalizumab has been licensed for use in severe allergic asthma. A search on the website clinicaltrials.gov reveals there are currently 109 clinical trials with Omalizumab of which 46 are for conditions other than asthma.Areas covered:In addition to asthma, Omalizumab has been investigated in various other conditions including perennial and seasonal allergic rhinitis (AR), peanut allergy, latex allergy, atopic dermatitis, chronic urticaria (CU), idiopathic anaphylaxis, mastocytosis, eosinophilic gastroenteritis and nasal polyposis. This review aims to look at the various randomised and non-randomised clinical trials, case series and case reports for the role of Omalizumab in conditions other than asthma. Numerous clinical trials have shown a positive light on the role of Omalizumab in conditions other than asthma.Expert opinion:We feel that the future of Omalizumab would include a more diverse range of clinical conditions, and future trials should not only look into the clinical usefulness but also the economic impact of using this interesting molecule.

Introduction:Patients with severe asthma have a significant unmet need with persistent symptoms and/or frequent exacerbations despite high intensity treatment. These severe unrelenting symptoms have a huge impact on heathcare resources due to frequent hospital admissions and requirement for intensive and expensive medications. There is a compelling need for more effective and safer therapies to help severe asthma sufferers to achieve adequate control of their disease.Areas covered:Expanding knowledge of innate and adaptive immune responses has led to development of new biologic approaches for severe asthma. Here, the authors will review the existing efficacy and safety data from clinical trials of some of the new biologic therapies that are in development for severe asthma. Their specific role in distinctively targeted subpopulations of severe asthmatics will be also discussed.Expert opinion:Defining and phenotyping severe asthma patients will become increasingly important as some patients who were previously classified as having severe asthma may become well-controlled with a targeted phenotype-specific treatment. However, pharmacoeconomic concerns should also be taken into account given the elevated acquisition costs of recombinant human monoclonals and of the diagnostic screening procedures for the identification of potential responders.

Despite optimal treatment, asthma symptoms in about 5–10% of patients remain poorly controlled. Apart from having an impact on their asthma-related quality of life and adverse effects of the medications used (especially corticosteroids), their severe symptoms also impact healthcare resources due to frequent admission and requirement for intensive medications use. The last decade has seen an improved understanding in the pathophysiology of the complex cellular and molecular networks involved in the inflammatory and immunological phenotype of severe asthma. This knowledge may help providing strategies by which these phenotypes operate and pave the way for drug development and individualized treatment.

Tobacco use and secondhand tobacco smoke exposure of children are a significant problem faced by pediatricians. This article reviews the recommendations of the 2008 update of the guideline Treating Tobacco Use and Dependenceand their application in the pediatric setting.

Background: Potassium channels represent a rich source of potential targets for therapeutic intervention. Clinically used potassium channel modulators comprise the sulfonylurea hypoglycemic agents (e.g., nateglinide, glipizide, mitiglinide), antiarrhythmic agents (dexsotalol, nifekalant, dofetilide, ibutilide), antianginal agents (nicorandil) and inotropic agents (levosimendan). Experimental evidence and preclinical models suggest the involvement of a number of potassium channels in respiratory diseases such as asthma and chronic obstructive pulmonary disease, supporting the prospects of potassium channel modulators as promising candidates in their therapeutic treatment. Objective: To present a survey on the most recent and relevant patents and patent applications of potassium channel modulators that have been claimed to be valuable for the treatment of chronic respiratory diseases: ATP-dependent K(KATP) channel openers, big-conductance K(BK) channel openers and intermediate-conductance K(IK) channel blockers. Methods: The review focuses on the most recent (January 2004 – June 2008) and relevant patents and patent applications in which respiratory diseases are included in the claims. Results/conclusion: KATPopeners, the pioneer potassium channel modulators investigated for the treatment of respiratory diseases, are nowadays object of lesser attention by the pharmaceutical industry, probably due to lack of clinical success experienced by big Pharma in the face of the large medicinal chemistry efforts directed to identify airway-selective drugs. Emerging attention can instead be perceived in the patent literature for BKCachannel openers and their potential use for the same therapeutic indications. Preclinical data support this interest, although clinical proof of concept has not yet been obtained due to the lack of potent and selective BKCadrug candidates. This scenario may, however, change in the near future, given the claims of recently-synthesized BKCaopeners superior to the benchmark NS1619. Until now, the only potassium channel modulating agent under clinical development in an airway indication is the IKCa1 channel blocker senicapoc (ICA-17043) from Icagen. This compound, which was investigated in Phase III trial for sickle cell anemia, is at present in Phase I for asthma.

Adenosine is a purine nucleoside of endogenous origin involved in a plethora of biological processes including neurotransmission, muscle contraction, cardiac function, haemostasis, vasodilatation, signal transduction, immune regulation, and inflammation/remodelling through specific stimulation of adenosine receptors. To date four subtypes of adenosine receptors have been identified; these are known as A1, A2A, A2B and A3 adenosine receptors. These are expressed on the cell membrane of a large variety of cell types, including inflammatory and structural cells, but their pattern of distribution, their specific function and affinity can vary in different cell types depending on the tissue milieu. This feature makes the understanding of adenosine regulated mechanisms in the pathogenesis of human diseases extremely challenging. Nonetheless, adenosine and its receptors are known to be pivotal in a wide range of disorders through modulation of specific biological responses in their respective organ systems. Adenosine and its receptors have been recently proposed to play a pro-inflammatory and immunomodulatory role in relation to the initiation and progression of several inflammatory disorders of the airways including asthma and chronic obstructive pulmonary disease (COPD). The objective of this article is to review the role of adenosine-receptor signaling in the respiratory system with special focus on chronic inflammatory airway diseases, such as asthma and COPD.

The adenosine receptors (A1, A2A, A2Band A3) are important and ubiquitous mediators of cellular signalling, which play vital roles in protecting tissues and organs from damage. Launched drugs include the adenosine receptor antagonists theophylline and doxofylline (both used as bronchodilators in respiratory disorders such as asthma), while several compounds are presently in clinical trials for a range of indications, including heart failure, Parkinson's disease, rheumatoid arthritis, cancer, pain and chronic obstructive pulmonary disease. A host of companies and institutions are addressing the huge potential for the development of selective adenosine receptor agonists and antagonists, so that it appears we are on the verge of a new wave of compounds approaching the market for many unmet medical needs. This review presents an analysis of the patenting activity in the area for 2006 and an interpretation and reflection on the developments that we can expect in the future.

Cigarette smoking plays a major role in the development of atherosclerosis and is associated with increased morbidity and mortality for coronary heart disease, stroke and peripheral vascular disease. In spite of the abundance of epidemiological evidence that links cigarette smoking to vascular disease, the pathologic mechanisms for such interaction are not clear. The endothelium is a major target organ that undergoes activation when exposed to common vascular triggers, including hypertension, hypercholesterolemia, hyperglycaemia and smoking. Changes in endothelial function may lead to a dysfunctional vascular phenotype characterized by anomalous responses of the vascular tone, abnormal endothelial proliferation and prothrombotic activation. Several studies have demonstrated that smoking may alter endothelial function by a direct toxic effect and consequently trigger haemostatic activation and thrombosis. In this article we will review the evidence that loss of normal endothelial function may result in a loss of the balance of the haemostatic system and in changes of the platelet physiology that may be relevant for the pathogenic effect of smoking on the development of atherothrombosis.

Recognition of the importance of leukotrienes in the pathogenesis of asthma has led to the development of leukotriene modifiers, the first new class of drugs for asthma treatment to become available since the introduction of inhaled corticosteroids. Nevertheless, despite their widespread use in clinical practice, the role of leukotriene modifiers in the management of asthma remains controversial. In the present article the clinical applications of this class of drugs have been critically reviewed based on recent evidence.

The increase in peripheral chemoreflex sensitivity in patients with obstructive sleep apnea (OSA) is associated with activation of autonomic nervous system and hemodynamic responses. Nasal CPAP (nCPAP) is an effective treatment for OSA, but little is known on its effect on chemoreflex sensitivity.

A growing body of evidence has emerged in support of a pro-inflammatory role for adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and COPD. The demonstration that adenosine enhances mast cell allergen-dependent activation, the notion that elevated levels of adenosine are present in chronically inflamed airways, and the results from exposure studies of nebulised adenosine showing dose-dependent bronchoconstriction in subjects with asthma and COPD, emphasise the importance of adenosine in the initiation, persistence and progression in these common inflammatory disorders of the airways. Adenosine exerts its manifold biological activities by interacting with at least four adenosine receptor subtypes. Selective activation or blockade of these sites is being exploited by the pharmaceutical industry in an attempt to generate novel therapies for asthma and COPD. This review article intends to address the potential role of adenosine in asthma and to put forward the idea that drugs that have been developed to selectively activate or downregulate adenosine receptor subtypes may constitute a considerable advance in the management of chronic airway inflammation.

This article examines recent work about the role of TNF-αand of selected Th1-related cytokines in asthma with particular emphasis on the therapeutic potential of blocking the biological activity of these mediators.

TNF-α (tumour necrosis factor-α) is known to play a critical role in the pathogenic mechanisms of a number of chronic inflammatory diseases, including RA (rheumatoid arthritis), Crohn's disease and psoriasis. The notion that TNF-α is released in allergic responses from both mast cells and macrophages via IgE-dependent mechanisms, the demonstration that elevated levels of TNF-α are frequently observed in bronchoalveolar fluid of asthmatic subjects undergoing allergen challenge and the results from exposure studies of TNF-α in vivo showing increases in airway responsiveness in both normal and asthmatic subjects emphasize the importance of TNF-α in the initiation of allergic asthmatic airway inflammation and the generation of airway hyper-responsiveness. Drugs targeting TNF-α have been developed to neutralize the deleterious effects of this inflammatory cytokine and have proved to be safe and effective in the treatment of patients with RA, Crohn's disease and psoriasis refractory to conventional treatments. Biological therapies blocking TNF-α are likely to constitute a considerable advance in the management of those difficult cases of asthma that are particularly resistant to typical treatment modalities. In this review article, we intend to address the potential role of TNF-α in asthma and to put forward the idea that drugs that have been developed to neutralize the deleterious effects of TNF-α may also be useful in the management of chronic severe asthma.

Bronchial hyperresponsiveness is present in virtually all patients with asthma and in more than two thirds of patients with chronic obstructive pulmonary disease. Thus far, methacholine and histamine are usually used to measure bronchial hyperresponsiveness. Both are direct stimuli, because they act directly on airway smooth muscle. Another possible stimulus to measure bronchial hyperresponsiveness is AMP. AMP is an indirect stimulus, because it acts via the release of histamine and other mediators from immunologically primed mast cells. There is increasing interest in the role of AMP as a bronchoconstrictor stimulus because it has been suggested that the concentration of AMP causing the FEV1to decrease by 20% (PC20AMP) may be used as a noninvasive marker of airway inflammation. The aim of this article was to review the literature assessing AMP's value in asthma and chronic obstructive pulmonary disease.

There is evidence that bronchial hyperresponsiveness to inhaled adenosine may be a better marker of airway allergic inflammation than bronchial hyperresponsiveness to other spasmogens. Here the authors review the most recent development in this area of rapidly evolving clinical research, focusing on the putative role of adenosine as a useful bronchoprovocant in asthma.

Background: Airway hyperresponsiveness (AHR) to pharmacologic stimuli and sputum eosinophils might be useful in the individual adjustment of long-term asthma management. However, it is not clear whether inhaled glucocorticosteroids (GCSs) provide greater protection against specific surrogate markers of airways inflammation than other means. In addition, detailed longitudinal assessment of changes in airway response with inhaled GCSs has never been carried out. Objectives: We compared changes in AHR to inhaled methacholine and adenosine 5′-monophosphate (AMP) after budesonide treatment in a randomized, double-blind, placebo-controlled, crossover study of patients with mild-to-moderate asthma. Subsequently, we undertook a separate study to examine the time course of the changes in AHR in more detail and the changes in sputum cell counts in relation to budesonide treatment. Methods: In the phase 1 of the study, patients undertook bronchial provocation studies with increasing doubling concentrations of methacholine (0.06 to 16 mg/mL) and AMP (3.125 to 800 mg/mL) before and after budesonide 0.8 mg/daily for 3 weeks. The bronchial responses to the inhaled agonists were expressed as the provocative concentration causing a 20% decline in FEV1(PC20). In phase 2 of the study, patients attended the laboratory on 12 separate occasions to investigate changes in PC20methacholine, PC20AMP, and sputum cell counts before, during, and after withdrawal of therapy with inhaled budesonide 0.8 mg/daily for 6 weeks. Results: Budesonide treatment for 3 weeks significantly attenuated the constrictor response by 0.8 ± 0.3 doubling doses for methacholine and by 2.6 ± 0.5 doubling doses for AMP. These changes were significantly different from each other (P= .003). Significant variation in PC20methacholine (P< .05) value, PC20AMP (P< .001) value, percentage of sputum eosinophils (P< .001), and percentage of sputum epithelial cells (P< .001) were observed throughout the longitudinal assessment of changes in airway response to budesonide. Compared with the other surrogate markers, PC20AMP appears to be useful in promptly detecting early inflammatory changes of the asthmatic airways; a significant change of 1.6 ± 0.3, 2.2 ± 0.3, and 2.8 ± 0.3 doubling doses of PC20AMP was observed at 1, 4, and 6 weeks, respectively, in the course of budesonide treatment. Conclusions: The present findings underline the exquisite selectivity of diverse surrogate markers of airway inflammation in response to inhaled budesonide. When compared with that to the other markers, AHR to inhaled AMP is an early and sensitive indicator of the beneficial anti-inflammatory effects of topical GCSs. (J Allergy Clin Immunol 2002;110:855-61.)

Exposure to elevated levels of particulate air pollution from motor vehicles is frequently associated with increased morbidity and mortality from cardiovascular conditions, lung cancer, and nonmalignant respiratory illnesses (e.g., asthma, bronchitis, respiratory tract infections). It appears, however, that less attention has been paid to the potential role of road traffic fumes in the induction of allergic conditions. Laboratory studies in humans and animals have shown that particulate toxic pollutants—particularly diesel exhaust particulates—can enhance allergic inflammation and can induce allergic immune responses. Most of these immune responses are mediated by the carbon core of diesel exhaust particulates. Polyaromatic hydrocarbons (e.g., anthracene, fluoranthene, pyrene, phenanthrene) are major chemical components of diesel exhaust particulates, and they have enhanced the production of immunoglobulin E. Although several large epidemiological studies have demonstrated a strong association between exposure to motor vehicle traffic emissions and allergic symptoms and reduced lung function, the evidence for the development of allergic sensitization from diesel exhaust particulates is less abundant than for the aforementioned associations. Recent comparisons of the prevalence of hay fever, as well as positive skin-prick tests, between citizens of former West and East Germany and between Hong Kong and China civilians, have demonstrated marked differences. Crucial variations in the level of particulate air pollution from motor vehicles in these countries may account for the observed increased prevalence of atopy. Although road-traffic pollution from automobile exhausts may be a risk factor for atopic sensitization, the evidence in support of this view remains conflictive. Some investigators have reported a clear association between the prevalence of allergy and road-traffic-related air pollution, whereas such a difference was not observed in other studies. Most discrepancies have been related to important variations in study design and methodology. In addition, inasmuch as exposure to ambient particles differs substantially in worldwide urban environments, perhaps qualitative—rather than quantitative—variations in particulate air pollution at different locations account for differences in the prevalence and/or severity of respiratory allergies.

Background:The c-erbB family of receptor tyrosine kinases act in a combinatorial fashion to regulate cell behavior. Disturbances in this system have been associated with neoplastic and inflammatory diseases. Objectives:Although expression of the epidermal growth factor receptor (EGFR; c-erbB1) is increased in the bronchial epithelium in asthma, there is no information on expression of other members of the c-erbB receptor and ligand family that can modulate EGFR function. Methods:Immunohistochemistry was used to compare expression of EGFR, c-erbB2, c-erbB3, epidermal growth factor, heparin-binding epidermal growth factor–like growth factor, and transforming growth factor α in bronchial biopsy specimens from normal and asthmatic subjects. Scrape-wounded monolayers of 16HBE 14o–cells were used as an in vitro model of damage and repair. Changes in EGFR, c-erbB2, and c-erbB3 distribution were measured by means of immunocytochemistry, whereas tyrosine phosphorylation was measured by means of immunoprecipitation and Western blotting. Results:Although epithelial staining for the EGFR was significantly increased in asthmatic epithelium (P< .001), there was no difference in staining for the other receptors and ligands studied. In scrape-wounded epithelial monolayers, tyrosine phosphorylation of EGFR, c-erbB2, and c-erbB3 occurred immediately after damage; however, only EGFR showed a change in expression in response to damage. Conclusions:Even though EGFR levels are increased in asthma, this is not linked to changes in expression of its activating ligands or other c-erbB receptors. Because bronchial epithelial cells respond to physical damage through activation of several c-erbB family members, the shift in favor of increased EGFR levels in asthma may lead to altered epithelial function by influencing the number and type of heterodimeric signaling complexes, assuming sufficient ligand availability. (J Allergy Clin Immunol 2002;109:75-81.)

Background:The epidermal growth factor (EGF) family of growth factors plays an important role in maintenance and repair in a variety of epithelial tissues. However, very little is known about coexpression of these factors and their receptors, the c-erbB family of receptor tyrosine kinases, in human nasal epithelium. Objective:We sought to investigate the expression of these molecules in cultured nasal epithelial cells and nasal mucosa from healthy individuals. Methods:Identification of c-erbB receptors and their ligands was sought by using reverse transcription PCR, Western blotting, and immunohistochemistry. Results:Messenger RNA encoding the EGF receptors (EGFR) c-erbB2 and c-erbB3, but not c-erbB4, was detected in primary cultures of human nasal epithelial cells. Transcripts encoding EGF, heparin-binding EGF, transforming growth factor (TGF) α, and amphiregulin were also detected. Receptor and ligand expression was confirmed by using immunocytochemical staining of the cells and Western blotting of the cell lysates. Immunohistochemical analysis of tissue sections obtained from biopsy specimens of nasal mucosa revealed intense membrane staining for the EGFR within the respiratory nasal epithelium, which was predominantly localized at the level of the columnar epithelial layers. Similar staining patterns were observed for c-erbB2 and c-erbB3 in the respiratory nasal epithelium. Evidence for EGF, transforming growth factor α, heparin-binding EGF, amphiregulin, and betacellulin immunostaining in the nasal epithelium was also obtained; their staining patterns paralleled that of EGFR immunostaining. Conclusion:Colocalization of c-erbB receptors and ligands establishes a basis on which to investigate c-erbB receptor– mediated effects in human nasal epithelium. (J Allergy Clin Immunol 2000;106:1124-31.)