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Tracheobronchial chondritis is a rare immune-related adverse event (irAE) associated with immune checkpoint inhibitors. We report a case wherein tracheobronchial chondritis occurred while administering nivolumab for recurrent hypopharyngeal squamous cell carcinoma (SCC) in a man diagnosed with T2N3bM0 stage IVB hypopharyngeal SCC. After treatment with cisplatin and radiotherapy followed by left and right neck dissection, local recurrence was observed in the hypopharynx. Because of the difficulty of salvage surgery, we administered 240 mg/body of nivolumab. After 9 cycles of nivolumab, the patient was judged to have complete response. After 10 cycles, he had cough and sputum, for which prompting us to perform imaging tests. Computed tomography (CT) showed edematous thickening around the trachea and bilateral bronchi and elevated amounts of adjacent subcutaneous fat tissue. Positron emission tomography-CT showed diffuse fluorodeoxyglucose uptake in the trachea and bilateral bronchi, bronchial endoscopy showed redness and swelling throughout the bronchi, and biopsy showed partial mucosal erosion, inflammatory cell (lymphocyte) infiltration, interstitial edema, and desmoplasia. The patient was diagnosed with tracheobronchial chondritis as an irAE resulting from administering anti-programmed death-1 monoclonal antibody. After four-day prednisolone treatment, his cough and sputum disappeared; after two weeks, tracheobronchial chondritis no longer appeared on CT., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K. Tsukahara has received grant support from Ono Pharmaceutical Co., Ltd and Bristol-Myers Squibb. The other authors have no actual or potential conflicts of interest or financial relationships to disclose.

Background: Indoor air pollution (IAP) is an emerging issue for both human and veterinary patients under the concept of 'One Health'. The association between IAP and respiratory disease in companion animals has been reported., Objectives: The present study investigated the relationship between quantifiable indoor air quality and clinical characteristics of naturally acquired bronchial/lung disease in pet dogs and cats., Methods: A total of 36 clinical cases (20 dogs and 16 cats) with naturally acquired bronchial/lung disease were prospectively recruited. Lower airway samples were collected and analysed, and clinical signs and the information from pulmonary function testing were examined. Indoor air quality was estimated by the average concentration of particles measuring ≤2.5 μm (PM2.5, μg/m 3 ) and volatile organic compounds (VOC, ppm) in the animals' domestic microenvironments., Results: Exposure to IAP was not found to be correlated with the severity of clinical signs, pulmonary function changes or bronchoalveolar lavage fluid cytology in cats with bronchial/lung disease. However, a hypercellular response in canine lower airways was found to be associated with poor indoor air quality, including unacceptable indoor PM2.5 levels (>35 μg/m 3 ) or increases in VOC concentration (>1 ppm) in places most commonly frequented by the dogs in the home., Conclusions: Poor indoor air quality may exacerbate airway disease in pets and should not be ignored in modern society., (© 2020 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

Background: There are few cases of multiple bronchial stenoses reported in the literature and none of the severity described here. The case is relevant due to its rareness, the pathophysiological insights derived, the successful interventional pulmonology strategies demonstrated, and as an example of a rare indication for high-risk lung transplantation., Case Presentation: A 47-year-old man developed multiple recurrent bronchial web-like stenoses five weeks after an episode of severe tracheo-bronchitis presumed secondary to a chemical inhalation injury which initially caused complete bilateral lung collapse necessitating veno-venous extracorporeal membrane oxygenation. The stenoses completely effaced bronchi in many locations causing severe type II respiratory failure requiring mechanical ventilation and bronchoscopic puncture / dilatation then ultimately bilateral lung transplantation., Conclusion: This very rare case highlights the morbid sequelae that can arise after catastrophic tracheobronchitis which now, in the era of extracorporeal membrane oxygenation, may be survivable in the short-term.

Lymphoproliferative disorders can occur in patients with autoimmune disorders who undergo long-term methotrexate therapy (MTX-LPD). Although the manifestations of MTX-LPD are diverse, little attention is paid to endobronchial involvement. We herein describe two patients with MTX-LPD who presented with parenchymal pulmonary tumors and endobronchial involvement of LPD; one had lymphomatoid gramulomatosis and the other LPD. The patients had no tumors adjacent to the endobronchial lesions. The endobronchial findings included multiple protruded mucosal lesions covered with white material, which was pathologically consistent with LPD. Recognition of the findings may help in making an earlier diagnosis of MTX-LPD in appropriate settings.

Since the start of Afghanistan combat operations in 2001, there has been an increase in complaints of respiratory illnesses in deployed soldiers with no previous history of lung disorders. It is postulated that deployment-related respiratory illnesses are the result of inhalation of desert particulate matter (PM) potentially acting in combination with exposure to other pro-inflammatory compounds. Why some, but not all, soldiers develop respiratory diseases remains unclear. Our goal was to investigate if human airway epithelial cells primed with IL-13, a type 2 inflammatory cytokine, demonstrate stronger pro-inflammatory responses to Afghanistan desert PM (APM). Primary human brushed bronchial epithelial cells from non-deployed, healthy subjects were exposed to APM, both with and without IL-13 pretreatment. APM exposure in conjunction with IL-13 resulted in significantly increased expression of IL-8, a pro-inflammatory cytokine involved in neutrophil recruitment and activation. Furthermore, expression of TLR2 mRNA was increased after combined IL-13 and APM exposure. siRNA-mediated TLR2 knockdown dampened IL-8 production after exposure to APM with IL-13. APM with IL-13 treatment increased IRAK-1 (a downstream signaling molecule of TLR2 signaling) activation, while IRAK-1 knockdown effectively eliminated the IL-8 response to APM and IL-13. Our data suggest that APM exposure may promote neutrophilic inflammation in airways with a type 2 cytokine milieu.

Inhaled corticosteroids (ICSs) have become the mainstay of asthma control. They are also recommended as an add-on therapy to long-acting beta agonists and anticholinergics in moderate to severe COPD with recurrent exacerbations. Ultimately this clinical practice has led to the widespread use of ICSs, which are supported by a more favorable side effect profile than that of systemic steroids., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

We experienced a case of life-threatening hypotension and bronchoconstriction associated with edema in a patient undergoing resection of a tumor of the right mandible following intravenous midazolam for induction of general anesthesia. We decided to postpone surgery for further examination of a possible drug-induced allergic reaction, and we rescheduled surgery for 1 week later. After administering H1 and H2 histamine antagonists, we administered a slow induction with sevoflurane in nitrous oxide and oxygen plus intravenous atropine sulfate after performing a test dose injection. We safely induced and maintained anesthesia with nitrous oxide, oxygen, and sevoflurane.

Aspiration of ferrous sulfate tablets is a rare and potentially serious condition that can lead to permanent airway stenosis. Diagnosis may be difficult, as presentation often includes nonspecific symptoms. Disease progression and treatment courses have been detailed in a limited number of publications. Herein, we report a case of severe bronchial stenosis that developed following aspiration of a ferrous sulfate tablet. To the best of our knowledge, this is the first reported attempt of laser fulguration to correct ferrous sulfate-induced bronchial stenosis.

Background: Tracheobronchial calcifications are considered a rare radiologic finding in children. Our clinical experience indicates that this finding is not infrequently seen among children with prosthetic heart valves who have been treated with warfarin sodium., Objective: We hypothesized that calcifications of the tracheobronchial tree are more common than previously reported in this patient population., Materials and Methods: We reviewed the medical records and imaging studies of children who underwent cardiac valve replacement at our institution to estimate the prevalence., Results: Tracheobronchial calcifications were identified on chest radiographs in 6 out of 17 children (35%), indicating that this imaging finding might be frequently overlooked., Conclusion: All children positive for tracheobronchial calcifications had been anticoagulated with warfarin sodium between the time of surgery and development of positive imaging findings. Our findings suggest that tracheobronchial calcifications are not uncommon in children treated with warfarin. Further investigation is necessary to determine wether there is a cause-effect relationship in these children.

A survey of 1097 workers of metallurgical enterprises showed that a chronic bronchitis is the most common bronchopulmonary disease (8,8-13,3%) in copper production workers There are much less detected chronic obstructive pulmonary disease (0.8-1.7%), asthma (0.3-0.4%), and only in copper-smelting plant workers - a toxic chemical pneumosclerosis (0.6%). Working conditions determine a higher prevalence of respiratory diseases and their development in less industrial work record in the manufacturing workers employed in electrolytic processing of copper and auxiliary shops. The conclusion about the need to improve working conditions and the use of more effective personal respiratory protection devices for copper production workers has been made.

Epidemiological studies have established a positive correlation between human mortality and increased concentration of airborne particulate matters (PM). However, the mechanisms underlying PM related human diseases, as well as the molecules and pathways mediating the cellular response to PM, are not fully understood. This study aims to investigate the global gene expression changes in human cells exposed to PM(10) and to identify genes and pathways that may contribute to PM related adverse health effects. Human bronchial epithelial cells were exposed to PM(10) collected from Saudi Arabia for 1 or 4 days, and whole transcript expression was profiled using the GeneChip human gene 1.0 ST array. A total of 140 and 230 genes were identified that significantly changed more than 1.5 fold after PM(10) exposure for 1 or 4 days, respectively. Ingenuity Pathway Analysis revealed that different exposure durations triggered distinct pathways. Genes involved in NRF2-mediated response to oxidative stress were up-regulated after 1 day exposure. In contrast, cells exposed for 4 days exhibited significant changes in genes related to cholesterol and lipid synthesis pathways. These observed changes in cellular oxidative stress and lipid synthesis might contribute to PM related respiratory and cardiovascular disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Adverse effects of drug therapy may induce a wide variety of bronchopulmonary disorders. The spectrum of drug induced lung and bronchial diseases include simple cough, bronchial obstruction, and obstructive bronchiolitis. Lung parenchyma may be affected by alveolitis/pneumonitis or lung fibrosis. Further damage patterns are noncardiac pulmonary oedema, diffuse alveolar damage, diffuse alveolar haemorrhage, eosinophilic lung diseases, pulmonary vascular disorders as well as pleural affections. These side effects rarely have pathognomonic features. Therefore they are relevant differential diagnoses of genuine pulmonary diseases. Diagnostics is based mainly on the verification of a compatible disease pattern, exclusion of differential diagnoses, and assessment of the temporal relationship and the consequences of drug abstention. Reexposure is rarely indicated. Strict elimination of the responsible drugs is the most important therapeutic measure. Additional drug therapy, mostly with glucocorticosteroids, may be indicated., (© Georg Thieme Verlag KG Stuttgart · New York.)

We report a case of 25-year-old woman with severe tracheobronchial necrosis caused by chlorine released from a mixture household cleaning agents. She subsequently exposed benzene while she was fixing the seats with benzene containing gum. The case was found interesting with its history, delayed diagnosis, bronchoscopic features, and fatal outcome. We presented its bronchoscopic and pathological images which has not been shown in the literature up to date.

We report the case of a 50-year-old male patient with a rare profile: bronchial casts associated with the use of pegylated interferon and ribavirin. The patient sought treatment in a pulmonology clinic with a history of progressive dyspnea for four months that had evolved to progressive cough followed by frequent and abundant elimination of bronchial casts. The patient was initially treated with bronchodilators, as well as with oral and inhaled corticosteroids. Fiberoptic bronchoscopy, bronchoalveolar lavage and sputum analysis were carried out but did not contribute to the elucidation of the diagnosis. The symptoms developed while the patient was receiving pegylated interferon and ribavirin for the treatment of hepatitis C. The symptoms resolved 30 days after the discontinuation of the treatment. To our knowledge, this is the first report of bronchial casts caused by the use of pegylated interferon and ribavirin.

Tracheobronchial obstruction is very uncommon in children and small infants. Stenosis and malacia, either congenital or acquired, are probably the most frequent diagnosis in this setting. Clinical symptoms are common to both airway anomalies and bronchoscopy plays a crucial role in the diagnostic work-up. Management is complex and surgeons involved in it should be familiar with multiple surgical and endoscopical techniques. Symptomatic short tracheal stenosis are best treated by means of resection and reconstruction, although endoscopic dilation or laser resection can be tried first in selected cases. In long tracheal stenosis, slide tracheoplasty is the surgical procedure of choice. Tracheobronchial malacia is usually self-limiting by the age of 3 years and most cases show mild symptoms that can be treated conservatively. In a small group of patients airway compromise is severe enough to require surgical or endoscopical treatment. Aortopexy or tracheostomy are the classic treatments for congenital tracheomalacia, but increasing experience with endoscopic airway stent placement in children is making this technique more attractive and popular. Acquired tracheomalacia is usually caused by a long-standing tracheostomy and if decannulation is impaired surgical treatment is mandatory.

Miners engaged into open-cast and underground extraction of copper-nickel ores in Kolsky Transpolar area have chronic bronchitis as a main nosologic entity among chronic bronchopulmonary diseases (19.1% of the workers). Considerably lower (4.0% of the workers) occurrence concerns chronic obstructive lung disease and bronchial asthma, both developed before the occupational involvement (1.3% of the workers). Complex of occupational and nonoccupational risk factors is connected mostly with smoking that increases COLD/CB risk 10.7-15.8-fold.

Asthma is a common condition that can substantially affect patients' quality of life. Although several drugs, most commonly beta-adrenergic agonists, alleviate symptoms of asthma, they may cause paradoxical bronchospasm or paradoxical bronchoconstriction. Levalbuterol hydrochloride-a pure form of the (R)-stereoisomer in racemic albuterol-eliminates the adrenergic properties that can cause such adverse effects. However, we report a case of paradoxical bronchoconstriction in a 36-year-old man who was recently diagnosed as having new-onset asthma and was treated with levalbuterol.

Background: Adenosine may cause bronchoconstriction in subjects with asthma or chronic obstructive pulmonary disease (COPD). Recent evidence suggests that this effect may be dependent on the severity of disease. This study investigates the tolerability of adenosine stress in patients with mild asthma or COPD undergoing myocardial perfusion scintigraphy., Methods and Results: In this case-control study patients with known or suspected mild asthma or COPD were pretreated with an inhaled beta(2)-adrenergic agonist and adenosine titrated up to the maximal dose of 140 microg x kg(-1) x min(-1) over a period of 6 minutes. The occurrence of side effects and test tolerability were compared between the airway disease group and 72 control subjects. Of 1261 patients, 124 had known or suspected airway disease; of these, 72 (58%) were suitable for adenosine stress. The proportion of tests completed as per protocol in the asthma/COPD group was similar to that of control subjects (93% vs 100%, P = .06). Dyspnea (n = 38 [53%] in asthma/COPD group vs n = 25 [35%] in control group, P = .03) and chest pain (n = 14 [19%] in asthma/COPD group vs n = 16 [22%] in control group, P = .7) were the most common side effects, and these were mostly mild and well tolerated. Bronchospasm occurred in 5 patients with asthma/COPD but reverted shortly after discontinuation of the adenosine infusion. Aminophylline was not required in any case., Conclusions: A stepwise 6-minute adenosine infusion with prophylactic beta(2)-adrenergic agonist is safe and well tolerated in patients with mild asthma or COPD.

A unique chronic obstructive pulmonary disease (COPD), provisionally called "mustard lung", which occurs as a late complication of sulfur mustard (SM) exposure among SM-exposed Iranians, is presently poorly characterized. This investigation evaluates p53 immunoreactivity in bronchial epithelium of individuals with histories of tobacco use and/or SM exposure, as a tool to help define mustard lung. In this study, 68 COPD patients were segregated into two groups, 35 mustard-exposed patients (including 8 smokers) and 33 unexposed patients (including 16 smokers). Disease severity was assessed with pulmonary function tests. p53 protein in bronchial tissue obtained as biopsies was quantitated by immunostaining. Among nonsmokers, 41.2% of unexposed subjects and 14.8% of exposed subjects expressed p53. Among smokers, 25% of the unexposed group and 50% of the exposed group expressed the protein. Initial data trends suggest an additive contribution of SM exposure and smoking to p53 immunoreactivity. These results illustrate the use of p53 immunoreactivity in the characterization of COPD, including mustard lung.

This report describes a death related to the abuse of and intoxication by mephenesin. To the best of our knowledge, this is the first report case of lethal intoxication involving solely mephenesin and reporting mephenesin blood concentrations. The victim was a 48-year-old woman found unconscious at home. Resuscitation was unsuccessful. Toxicological analysis was performed on a blood sample collected during resuscitation. The results being negative, the body was exhumed for an autopsy, which revealed bronchial inhalation syndrome. Analysis in a second laboratory has revealed the presence of mephenesin in samples collected during autopsy. No other drug/toxin was found, and alcohol was negative. Reanalysis of the peripheral blood collected during resuscitation found a mephenesin concentration of 15.81 microg/mL (15-fold greater that the maximum concentration that would result from a single intake of a 500 mg formulation). The pathologist has concluded on a bronchial inhalation syndrome consecutive to a mephenesin overdose as the cause of death. The manner of this death is discussed in the light of the toxicological hair analysis and the medical past of the victim.

Rationale: Mustard gas primarily affects the eyes, skin, and particularly the respiratory tract. Tracheobronchomalacia (TBM) and air trapping are often observed in high-resolution computerized tomography (HRCT) scans of the chest of mustard gas-exposed patients., Objectives: To examine the frequency and severity of TBM in a group of Iranian wartime mustard gas-exposed victims, and to investigate the correlation between TBM and air trapping in these cases., Materials and Methods: Chest HRCT films obtained from 300 randomly selected subjects who had been exposed to mustard gas 15.5 yr previously were reviewed to determine the existence of TBM and air trapping. The HRCT films of a healthy control group were also analyzed for comparison., Results: Out of 300 reviewed cases, 13 had TBM. From these 13 TBM cases, 11 (85%) showed air trapping with mean score of 5.5. In the control group, 5 (25%) of 20 subjects showed air trapping, with mean score of 0.6. The total air trapping was significantly higher in the TBM group (p < 0.001). There was an association between the severity of tracheomalacia and air trapping in the TBM group (p = 0.01, r = 0.69), but no association was observed between severity of bronchomalacia and air trapping., Conclusion: The results show that air trapping and TBM are correlated, both as long-term sequelae in mustard gas-exposed cases. Because air trapping is highly suggestive of bronchiolitis obliterans, we conclude that both bronchiolitis obliterans and TBM are caused by a single underlying process affecting small and large airways, respectively, in this group of patients.

In response to inflammation or injury, airway epithelial cells express inducible genes that may contribute to allergen-induced airway remodeling. To determine the contribution of epithelial cell NF-kappaB activation to the remodeling response, we generated CC10-Cre(tg)/Ikkbeta(delta/delta) mice in which NF-kappaB signaling through IkappaB kinase beta (IKKbeta) is selectively ablated in the airway epithelium by conditional Cre-recombinase expression from the Clara cell (CC10) promoter. Repetitive ovalbumin challenge of mice deficient in airway epithelial IKKbeta prevented nuclear translocation of the RelA NF-kappaB subunit only in airway epithelial cells, resulting in significantly lower peribronchial fibrosis in CC10-Cre(tg)/Ikkbeta(delta/delta) mice compared with littermate controls as assessed by peribronchial trichrome staining and total lung collagen content. Levels of airway mucus, airway eosinophils, and peribronchial CD4+ cells in ovalbumin-challenged mice were also reduced significantly upon airway epithelial Ikkbeta ablation. The diminished inflammatory response was associated with reduced expression of NF-kappaB-regulated chemokines, including eotaxin-1 and thymus- and activation-regulated chemokine, which attract eosinophils and Th2 cells, respectively, into the airway. The number of peribronchial cells expressing TGF-beta1, as well as TGF-beta1 amounts in bronchoalveolar lavage, were also significantly reduced in mice deficient in airway epithelium IKKbeta. Overall, these studies show an important role for NF-kappaB regulated genes in airway epithelium in allergen-induced airway remodeling, including peribronchial fibrosis and mucus production.

Mustard gas or sulfur mustard (SM) is an alkylating chemical warfare agent that was widely used during the World War I and in the Iran-Iraq conflict. We aimed to study late toxic effects of SM on the respiratory system of severely intoxicated Iranian veterans. Respiratory examination, spirometry, arterial blood gas (ABG) analysis, and high resolution computed tomograpghy (HRCT) of the chest were performed on all severely SM-poisoned veterans in the province of Khorasan, Iran. HRCT abnormalities were classified into four grades based on the number of lung lobes involved. ABG and spirometric results were compared with each other, as well as, with the severity grades of HRCT abnormalities, using Spearman's rank correlation test. Forty male subjects with confirmed SM poisoning 16 to 20 years ago, were studied. Main respiratory complications were diagnosed as chronic obstructive pulmonary disease (COPD) (35%), bronchiectasis (32.5%), asthma (25%), large airway narrowing (15%), pulmonary fibrosis (7.5%), and simple chronic bronchitis (5%) patients. While there was a significant correlation (p<0.05) between ABG and spirometric results, the severity grades of HRCT abnormalities revealed a significant correlation (p<0.05) only with PaO2. We concluded that SM-induced respiratory complications tend to progress over the years. While spirometry is a valuable diagnostic tool for evaluation of pulmonary impairment during regular follow-ups, ABG and HRCT are more objective and should be more considered for evaluation of the severity and for diagnosis of the respiratory complications.

Objective and Design: We examined the reversibility of several changes in the lungs and airways of mice immediately after exposure to ovalbumin aerosol and after a period of recovery breathing clean air., Methods: Mice were exposed for 1, 2, 4, 6, 8, or 10 weeks, with recovery in clean air for 1-3 weeks., Results: Airway collagen content, exhaled NO, airway mucous cell hyperplasia, and lung lavage inflammatory cell content increased upon exposure to ovalbumin aerosol. All parameters except airway fibrosis decreased partially or completely to control values with recovery in clean air., Conclusions: Airway mucous cell hypertrophy and hyperplasia appear to be completely reversible after recovery in clean air, while exhaled NO and airway inflammation appear to be mostly reversible, except for persistence of lymphocytes in the lung lavage fluid. Airway fibrosis appears to be reversible when mice are exposed to ovalbumin aerosol for periods of up to 4 weeks of exposure, but becomes irreversible after 6 or more weeks of exposure.

The effect of sidestream tobacco smoke combined with other pollutants is largely unknown. Previously, we found that distal airway epithelial repair was inhibited in mice exposed to sidestream tobacco smoke (TS) for 5 days followed by single exposure to naphthalene (NA), a common polycyclic aromatic hydrocarbon found in cigarette smoke, diesel exhaust, and pesticide formulations. The main injury target of NA is the nonciliated (Clara) bronchiolar cell. NA injury normally resolves in two weeks. Repair in mice exposed to TS and NA was unresolved in the distal bronchioles 14 days post-NA injury. We hypothesized that repair inhibition persisted as a first step towards long-term airway remodeling and expanded the previous study by evaluating repair 21 days after acute NA injury. Repair was evaluated using high resolution histopathology, TEM, and quantitative morphometry. In animals exposed to TS and NA, repair was still impaired; re-differentiation of Clara cells at the bronchoalveolar duct junction was incomplete, indicating repair was continuing. Compared to 14 days post-NA-injury, repair at 21 days post-NA treatment was more extensive. Animals exposed only to TS had epithelium similar to controls. While TS exposure impairs bronchiolar epithelial repair after NA exposure, this effect appears to be slowly resolving over time.

Sulfur mustard inhalation leads to different respiratory complications. In this article, we describe late stenotic effects of mustard gas inhalation on major airways. About 15 yr after exposure, suspect cases suffering from severe respiratory disorders underwent complete workup for central airway stenosis. Patients were evaluated with bronchoscopy and tracheal computerized tomography scan. The mean age of patients was 43+/-8 yr. The mean exposure time was 16+/-0.7 yr. The mean time between injury and diagnosis of tracheobronchial stenosis was 11.7+/-4.8 yr. Among the 33 referred cases with no other risk factor of stenosis, 8 cases had significant stenosis in their major airways, confirmed by tracheal computerized tomography scan and bronchoscopy. We conclude that direct toxic effects of sulfur mustard can lead to tracheobronchial stenosis with different degrees of involvement ranging from diffuse tracheal stenosis to stenosis of the isolated left main bronchus or glottic and subglottic stenosis.

Lipopolysaccharide (LPS) is known to generate nitric oxide (NO) in the airway through the activation of nitric-oxide synthase (NOS). The functional consequences of this on the inflammatory response are not clear, with conflicting data published. In the clinic, exhaled NO (ex-NO) is used as a noninvasive biomarker to assess the extent of airway inflammation. It is proposed that monitoring levels of ex-NO could be a useful guide to determining the effectiveness of disease modifying therapies. The aim was, using pharmacological tools, to determine the role of NO in an aerosolized LPS-driven animal model of airway inflammation by assessment of ex-NO, neutrophilia, and inflammatory biomarkers, using a nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), and a selective inducible NOS (iNOS) inhibitor, N-3 (aminomethyl)benzyl)acetamidine (1400W). Real-time mRNA analysis of the lung tissue indicated an increased gene expression of iNOS following LPS challenge with minimal impact on constitutive NOS isoforms. LPS induced an increase in ex-NO, which appeared to correlate with the increase in iNOS gene expression and airway neutrophilia. Treatment with l-NAME and 1400W resulted in comparable reductions in ex-NO, a reduction in airway neutrophilia, but had little impact on a range of inflammatory biomarkers. This study indicates that the LPS-induced rise in ex-NO is due to enhanced iNOS activity and that NO has a role in airway neutrophilia. Additionally, it appears using ex-NO as a guide to monitoring airway inflammation may have some use, but data should be interpreted with caution when assessing therapies that may directly impact on NO formation.

Children's exposure to air pollution is a special concern because their immune system and lungs are not fully developed when exposure begins, raising the possibility of different responses than seen in adults. In addition, children spend more time outside, where the concentrations of pollution from traffic, powerplants, and other combustion sources are generally higher. Although air pollution has long been thought to exacerbate minor acute illnesses, recent studies have suggested that air pollution, particularly traffic-related pollution, is associated with infant mortality and the development of asthma and atopy. Other studies have associated particulate air pollution with acute bronchitis in children and demonstrated that rates of bronchitis and chronic cough declined in areas where particle concentrations have fallen. More mixed results have been reported for lung function. Overall, evidence for effects of air pollution on children have been growing, and effects are seen at concentrations that are common today. Although many of these associations seem likely to be causal, others require and warrant additional investigation.

Background: The etiology of acute chest syndrome, the most severe complication of the sickle cell crisis, is unknown., Objective: Our objective was to assess exposure to morphine as an etiologic factor for acute chest syndrome in sickle cell disease., Methods: A post hoc analysis of a randomized controlled trial comparing oral with continuous infusion of morphine was performed. Children (aged 5-17 years) with sickle cell crisis were randomized to receive oral sustained-release morphine, 1.9 mg. kg(-1). 12 h(-1), or a continuous intravenous infusion of morphine at 0.04 mg. kg(-1). h(-1) by use of a double-blind, placebo-controlled design. In a subgroup of 15 patients, the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide were also studied., Results: At baseline, demographic and physiologic characteristics were similar between groups. There were no differences in the number of previous rescue doses per day, painful sites per episode, physician contacts per year, and hospitalizations per year between treatment arms. There was a 2-fold higher morphine area under the concentration-time curve at steady state (AUC(ss)) and a 3-fold higher morphine-6-glucuronide AUC(ss) with oral morphine than with a continuous intravenous infusion of morphine (P <.001 and P <.006, respectively). New onset of acute chest syndrome was 3-fold more prevalent in the oral group (57%) versus the continuous intravenous infusion group (17%) (P <.001)., Conclusions: The risk of acute chest syndrome is significantly associated with high systemic exposure to morphine and its active metabolite morphine-6-glucuronide after oral administration of slow-release morphine. Morphine may facilitate respiratory deterioration by eliciting a decrease in oxygen saturation, by inducing histamine release, or through an as-yet-unidentified mechanism. The safe systemic exposure to morphine in terms of area under the concentration-time curve should be further studied in children with sickle cell disease.

Recent advances in high-density DNA microarray technique allow the possibility to analyze thousands of genes simultaneously for their differential gene expression patterns in various biologic processes. Through clustering analysis and pattern recognition, the significance of these differentially expressed genes can be recognized and correlated with the biologic events that may take place inside the cell and tissue. High-density DNA microarray nylon membranes were used to explore gene expression and regulation associated with smoke- and hydrogen peroxide-induced injury and repair in differentiated human bronchial epithelial cells in vitro. At least three phases of change in gene expression could be recognized. The first phase seems to be an immediate event in response to oxidant injury. This phase includes the induction of bcl-2 and mdm2 genes that are involved in the regulation of apoptosis, and the mitogen-activated protein kinase phosphatase 1 that functions as a regulator for various mitogen-activated protein kinase activities. The second phase, usually 5 h later, includes the induction of various stress proteins and ubiquitin, which are important in providing the chaperone mechanism and the turnover of damaged macromolecules. The third phase, which is 5 to 10 h later, includes the induction of genes that seem to be involved in reducing oxidative stress by metabolizing the cellular level of reactive oxygen species. In this phase, enzymes associated with tissue and cell remodeling are also elevated. These results demonstrated a complex gene expression array by bronchial epithelial cells in response to a single insult of oxidants that are relevant to environmental pollutants.

We report a case of a 42-year-old man who fell in a vat of hydrochloric acid, resulting in ingestion and aspiration of acid. Initially, he suffered from a chemical pneumonitis and GI burns. He was released from the hospital without complications, only to return with signs and symptoms consistent with asthma. Evaluation revealed multiple areas of large airway stenosis, resulting from the chemical burns. The stenoses were treated with multiple stents.

Background: Inhaled zanamivir is indicated for treatment of uncomplicated acute illness due to influenza A and B viruses in patients aged > or = 12 years who have been symptomatic for no more than 2 days., Objective: The primary objective of this study was to estimate the incidence of adverse respiratory events among zanamivir-treated patients under conditions of usual care., Methods: The Ingenix research database includes insurance claims for all dispensations, inpatient and outpatient services, and procedures including the associated diagnoses and costs for a subset of all enrolled UnitedHealthcare members. We identified all persons with a dispensation of zanamivir recorded between October 1, 1999, and April 30, 2000. We captured medical and pharmaceutical claims data for the 6 months before the dispensation to obtain information about comorbidities, overall health status, and respiratory events. Medical and hospital record abstraction and clinical review served to confirm inpatient/emergency department (ED) events. We also examined the records of an approximately 10% random sample of patients treated for a potential respiratory event in an outpatient/ physician office visit during the 10-day follow-up period. Respiratory events not sufficiently severe to result in medical care were not captured in this study., Results: A total of 5498 eligible zanamivir dispensations contributed by 5450 patients (2911 females, 2539 males; mean age, 38.8 years), with 40 confirmed inpatient/ED respiratory events, were included in the study. Of these 40 events, 31 were pneumonia, bronchitis, or exacerbations of existing chronic respiratory disease; none required intubation or ventilation. No events occurred on the dispensation date. The overall risk for an inpatient/ ED respiratory event was 0.7 per 100 episodes (95% CI, 0.5-1.0). Seven events of wheezing or shortness of breath were not an obvious extension of the original influenza-like illness or of a complicating bronchitis (risk = 0.13 per 100 episodes; 95% CI, 0.06-0.26)., Conclusions: No immediate or severe bronchoconstrictive responses occurred among 5498 zanamivir dispensations. The overall risk for any respiratory event was low, and none was sufficiently severe to suggest respiratory failure.

To ascertain whether cessation of smoke exposure would decrease small-airway secretory-cell metaplasia, guinea pigs were exposed to daily cigarette smoke using a nose-only exposure system for 4 and 8 mo; an additional group was exposed to smoke for 4 mo and then air recovery for 4 mo ("ex-smokers"). Numbers of secretory cells per millimeter of basement membrane were calculated for each bronchiole from measurements of histologic sections stained with Alcian blue/periodic acid Schiff, and cumulative histograms were constructed. Smoke exposure was associated with a significant increase in numbers of secretory cells at 4 mo and 8 mo, although there was no increase in numbers beyond the 4-mo exposure period. In the ex-smoking group, secretory cells were reduced compared to the 4- or 8-mo smoking group, but continued to be greater than controls. We conclude that, in a guinea pig model, smoking produces secretory-cell metaplasia in the airways and that smoking cessation allows partial recovery of normal structure.

The relationship between gastroesophageal reflux and asthma remains unclear. The aim of this study was to analyze the effect of bronchial obstruction on lower esophageal sphincter (LES) motility and reflux in patients with asthma. LES motility and esophageal pH were assessed in eight subjects with intermittent asthma and eight healthy volunteers during three consecutive 30-minute periods: baseline, methacholine-induced bronchospasm, and after inhalation of the beta2-agonist salbutamol. Healthy subjects inhaled 2 mg of methacholine, whereas subjects with asthma inhaled the dose of methacholine causing a 15% fall in FEV(1), as determined by a previous methacholine challenge. LES motility, esophageal pH, and FEV(1) were not significantly different between the three periods in healthy subjects. In patients with asthma, methacholine induced a 21.9 +/- 2.6% decrease in FEV(1) and a concomitant increase in the rate of transient LES relaxation (TLESR) and reflux episodes. Inhalation of salbutamol decreased the rate of TLESRs but not the number of reflux episodes. We conclude that in patients with asthma, methacholine-induced bronchospasm increases the rate of TLESR and the number of reflux episodes. These results support the belief that, in asthma, bronchial obstruction may be responsible for reflux or may aggravate reflux through a mechanism that remains to be further clarified.

Background: Angiotensin-converting enzyme (ACE) inhibitors are often associated with an increased incidence of cough and bronchial responsiveness that may cause further deterioration of patients with impaired pulmonary function., Objective: To review the available literature on the incidence of cough and bronchial responsiveness associated with ACE-inhibitor therapy in patients with asthma, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF)., Data Sources: Literature was accessed through MEDLINE (1985-September 2001). Key search terms included cough, bronchospasm, asthma, congestive heart failure, chronic obstructive pulmonary disease, ACE inhibitors, and angiotensin II receptor blockers., Data Synthesis: The literature reports several cases of increased bronchial responsiveness associated with ACE inhibitors. Larger, controlled studies evaluating the increased risk in patients with pulmonary dysfunction are limited. Data from these trials are summarized in this article., Conclusions: The literature shows that patients with primary airway disease such as asthma and COPD are not at an increased risk of developing cough or bronchoconstriction as a result of ACE-inhibitor therapy. Despite the ability of ACE inhibitors to improve exercise tolerance, perfusion, and gas transfer, patients with CHF may be at higher risk of developing cough than the general population. Whether this cough is attributed to ACE inhibition or increased left-ventricular dysfunction remains uncertain. If increased bronchial responsiveness does occur, angiotensin II receptor antagonists are another reasonable option.

Understanding cellular repair mechanisms in vivo has been advanced through the use of well-defined injury and repair models and their application to knockout and transgenic animals, primarily mice generated in a variety of background strains. However, little is known concerning the effect that mouse strain itself has on the interpretation and comparability of observations when the strain used for genetic manipulation is not the strain used to develop the model. We compared acute bronchiolar injury and repair in three strains of mice used in knockout mouse development (C57BL/6, 129/TerSv, and 129/SvEv) to the model strain (Swiss Webster) after treatment with the same dose of naphthalene and sacrificed at 1, 2, 4, 7, and 14 days after treatment. Extent of Clara cell toxicity and exfoliation was identical in the distal airways of all strains. There were significant strain-related differences in ciliated cell squamation, initiation and duration of proliferation, epithelial differentiation, and time to completion of epithelial repair. We conclude that ciliated cells play a prominent role in repair of distal airway injury, but that all phases of the repair process differ by strain. In addition, our findings reinforce that control animals must be of the same strain, ideally litter mates, when transgenic or knockout mice are used for the study of airway repair processes and mechanisms.

In asthma patients, microaspiration of acid into the lower airways (ie, airway acidification) causes such respiratory responses as cough and bronchoconstriction. The mechanism of bronchoconstriction induced by airway acidification is unknown, although evidence is emerging that increasing proton concentrations in airway tissues can activate a subpopulation of primary sensory neurons, so-called capsaicin-sensitive primary sensory neurons, that contain such neuropeptides as the tachykinins substance P (SP) and neurokinin A (NKA). Protons activate a capsaicin-operated channel/receptor, located in the afferents of capsaicin-sensitive neurons, with the subsequent opening of ion channels that are permeable to sodium, potassium, and calcium ions. This event initiates a propagated action potential that antidromically depolarizes collateral fibers and triggers neuropeptide release from nerve fiber varicosities. The tachykinins SP and NKA, released from terminals of primary sensory neurons in peripheral tissues, cause all the major signs of inflammation (neurogenic inflammation) by means of activation of NK(1) and NK(2) receptors. Exposure of the airways to acidic solutions stimulates sensory nerve endings of capsaicin-sensitive sensory neurons and causes different airway responses, including bronchoconstriction. Recently, the NK(2), and to a lesser extent the NK(1), receptors have been shown to be involved with citric acid-induced bronchoconstriction in the guinea pig, which is in part mediated by endogenously released bradykinin. Tachykinins and bradykinin, released by airway acidification, could also modulate citric acid-induced bronchoconstriction by their ability to subsequently release the epithelially derived bronchoprotective nitric oxide (NO). Further study with selective tachykinin NK(1) and NK(2) agonists demonstrated that only the septide-insensitive tachykinin NK(1) receptor releases NO. Thus, bronchoconstriction induced by citric acid inhalation in the guinea pig, mainly caused by the tachykinin NK(2) receptor, is counteracted by bronchoprotective NO after activation of bradykinin B(2) and tachykinin NK(1) receptors in airway epithelium. If a similar mechanism is involved in the pathogenesis of bronchial asthma associated with gastroesophageal reflux in the respiratory tract, new therapeutic strategies should be investigated.

Drug abuse is a growing problem in industrialized countries, opening the way to new diseases of the respiratory tract. It has been demonstrated that regular inhalation of cannabis has the same consequences as tobacco smoking. The same cannot be said for other drugs. Cocaine, amphetamines or crack expose the patient to particular toxic effects: in addition to barotrauma related to the administration route, syndromes of acute respiratory distress have been described. These result either from bronchial reactions, asthma exacerbation or eosinophil bronchopneumonia, or alveolar involvement: intra-alveolar bleeding, pulmonary edema or organized pneumonia. Respiratory complications induced by opiates, often used in injections, are related to central alveolar hypoventilation and/or the development of injury from pulmonary edema or pneumonia. The pathophysiology of these lesions is not perfectly understood. Besides these specific conditions, infection is a major problem in drug abusers, irrespective of the drug: bacterial pneumonia, tuberculosis, HIV infection are much more frequent in this high-risk group. Finally repeated intravenous injections of various drugs designed for oral intake can lead to severe complications such as pulmonary hypertension or toxic interstitial lung disease. Summarizing, respiratory diseases in drug abuses can take on a wide range of quite complex presentations. Occasional or regular use of illicit drugs can lead, not exceptionally, to severe respiratory complications requiring rapid management. Knowledge of the principal complications and the appropriate diagnostic procedures is indispensable.

Acute bronchial mucosal sloughing related to Toxic Epidermal Necrolysis (Lyell syndrome) is widely reported in literature. On the contrary severe respiratory involvement is rare in post-infectious or toxic Epitheliolysis (Stevens-Johnson syndrome). There is no well-known predictive sign of bronchial epithelium involvement. An 18-year-old patient was admitted for Stevens-Johnson syndrome related to sulfasalazine (salazosulfapyridine). There were no respiratory signs. An acute respiratory failure occurred 36 hours after from admission due to an obstructive and desquamative necrosis of the tracheobronchial epithelium. We purpose that a fiberoptic laryngoscopy should be performed even in non-dyspneic patients suffering from Stevens-Johnson syndrome if hypersecretion is present. Fiberoptic bronchoscopy can be helpful in these cases.