Progressive Airway Disease Research Articles

Proteases, cystic fibrosis and the epithelial sodium channel (ENaC)

Proteases perform a diverse array of biological functions. From simple peptide digestion for nutrient absorption to complex signaling cascades, proteases are found in organisms from prokaryotes to humans. In the human airway, proteases are associated with the regulation of the airway surface liquid layer, tissue remodeling, host defense and pathogenic infection and inflammation. A number of proteases are released in the airways under both physiological and pathophysiological states by both the host and invading pathogens. In airway diseases such as cystic fibrosis, proteases have been shown to be associated with increased morbidity and airway disease progression. In this review, we focus on the regulation of proteases and discuss specifically those proteases found in human airways. Attention then shifts to the epithelial sodium channel (ENaC), which is regulated by proteolytic cleavage and that is considered to be an important component of cystic fibrosis disease. Finally, we discuss bacterial proteases, in particular, those of the most prevalent bacterial pathogen found in cystic fibrosis, Pseudomonas aeruginosa.

Neonatal pulmonary interstitial glycogenosis in a patient with Hunter syndrome

In 2004, we reported on a neonate with pulmonary interstitial glycogenosis (PIG), with favorable outcome at the age of 19 months when the case report was published [8]. However, at the age of 3 years, hepatosplenomegaly and a mild limitation in joint mobility was detected by clinical examination. Hunter syndrome (mucopolysaccharidosis (MPS) type II) was diagnosed. In the following years, the patient presented with frequent upper respiratory infections, moderate hearing loss, and umbilical hernia, common findings in patients with MPS II. At the age of 8 years, the patient’s lung function tests show a severe combined obstructive/restrictive pattern with a forced vital capacity of 70% predicted and a FEV1 of 30% predicted. Infectious exacerbations usually necessitate oral steroid treatment (median of 3 periods annually). The patient receives enzymtherapy (Elaprase® = idursulfase), which stabilized his neurodevelopmental status but not his respiratory problems. It is unclear whether neonatal PIG accompanies MPS II or not. Classically, in MPS II, pulmonary dysfunction manifests primarily by progressive airway disease, frequent upper respiratory tract infections being one of the earliest findings [6]. Clinical features appear between 2 and 4 years of age, newborn infants usually being normal. The biochemical cause is a deficiency in the activity of the lysosomal enzyme, iduronate-2-sulfatase, resulting in reduced degradation of dermatan sulfate and heparan sulfate. Accumulation of these glycosaminoglycans in the soft tissues of the respiratory system leads to narrowing of the trachea, eventually leading to progressive obstructive airway disease, gradually involving the lower airways [5]. Atelectasis and tracheobronchomalacia have also been reported to be associated with MPS II [7]. Glycogen is required to support epidermal mitosis in embryonic respiratory epithelium and other tissues with

Moraxella catarrhalisacquisition, airway inflammation and protease-antiprotease balance in chronic obstructive pulmonary disease

BackgroundMoraxella catarrhalis causes approximately 10% of exacerbations in chronic obstructive pulmonary disease (COPD) and also colonizes the lower airway in stable patients. Little is known about the effects of colonization by M. catarrhalis on airway inflammation and protease-antiprotease balance, and how these changes compare to those seen during exacerbations. Since COPD is a progressive inflammatory disease, elucidating the effects of bacterial colonization and exacerbation on airway inflammation is relevant to understanding disease progression in COPD. Our aims were (1) Analyze changes in airway inflammation in colonization and exacerbation of COPD due to M. catarrhalis; (2) Explore protease-antiprotease balance in colonization and exacerbation due to M. catarrhalis. Our hypothesis were (1) Acquisition of a new strain of M. catarrhalis in COPD increases airway inflammation from baseline and alters the protease-antiprotease balance towards a more proteolytic environment; (2) These changes are greater during exacerbations associated with M. catarrhalis as compared to colonization.MethodsThirty-nine consecutive COPD patients with 76 acquisitions of a new strain of M. catarrhalis over a 6-year period were identified in a prospective study. Seventy-six pre-acquisition sputum supernatant samples, obtained just before acquisition of M catarrhalis, and 76 acquisition samples (34 were associated with exacerbation, 42 with colonization) were analyzed for IL-8, TNF-α, Neutrophil Elastase (NE) and Secretory leukocyte protease inhibitor (SLPI). Changes were compared in paired samples from each patient.ResultsIL-8, TNF-α and NE were significantly elevated after acquisition of M. catarrhalis, compared to pre-acquisition samples (p =< 0.001 for all three). These changes were present in colonization (p = 0.015 for IL-8; p =< 0.001 for TNF-α and NE) as well as in exacerbation (p =< 0.001 for all three), compared to pre-acquisition levels. SLPI was significantly lower after acquisition (p =< 0.001), in colonization (p =< 0.001) as well as in exacerbation (p = 0.004), compared to pre-acquisition levels. SLPI levels correlated negatively with NE levels (R2 = 0.07; p = 0.001).ConclusionAcquisition of M. catarrhalis in COPD causes increased airway inflammation and worsening protease-antiprotease imbalance during exacerbations and also in colonization, even in the absence of increased symptoms. These effects could contribute to progression of airway disease in COPD.

Relapsing Polychondritis and Airway Involvement

To assess the prevalence and characteristics of airway involvement in relapsing polychondritis (RP). Retrospective chart review and data analysis of RP patients seen in the Rheumatology Clinic and the Complex Airway Center at Beth Israel Deaconess Medical Center from January 2004 through February 2008. RP was diagnosed in 145 patients. Thirty-one patients had airway involvement, a prevalence of 21%. Twenty-two patients were women (70%), and they were between 11 and 61 years of age (median age, 42 years) at the time of first symptoms. Airway symptoms were the first manifestation of disease in 17 patients (54%). Dyspnea was the most common symptom in 20 patients (64%), followed by cough, stridor, and hoarseness. Airway problems included the following: subglottic stenosis (n = 8; 26%); focal and diffuse malacia (n = 15; 48%); and focal stenosis in different areas of the bronchial tree in the rest of the patients. Twelve patients (40%) required and underwent intervention including balloon dilatation, stent placement, tracheotomy, or a combination of the above with good success. The majority of patients experienced improvement in airway symptoms after intervention. One patient died during the follow-up period from the progression of airway disease. The rest of the patients continue to undergo periodic evaluation and intervention. In this largest cohort described in the English language literature, we found symptomatic airway involvement in RP to be common and at times severe. The nature of airway problems is diverse, with tracheomalacia being the most common. Airway intervention is frequently required and in experienced hands results in symptom improvement.

Pulmonary Complications of Cystic Fibrosis

Earlier diagnosis, treatment of exacerbations, and the use of long-term therapies have all improved the lifespan of patients with cystic fibrosis (CF). However, the natural history of CF airways disease remains one of worsening bronchiectasis and obstructive airways impairment. The progression of airways disease leads to eventual respiratory failure, but some will suffer other acute respiratory complications that require intervention, including pneumothorax, massive hemoptysis, and respiratory failure. Here I discuss the pathophysiology of these complications and the patient-related and treatment-related factors associated with their occurrence. Knowledge of these associations may play great importance in treatment decisions regarding the care of the patient and the respiratory therapist should be aware of the implications. Since disease severity is associated with all 3 conditions, aggressive treatment of the underlying condition is imperative, which includes the performance of airway-clearance therapies. Though some might argue that airway-clearance therapies might aggravate or even precipitate complications such as hemoptysis and pneumothorax, others will defend that there are airway-clearance therapies that might be safely performed. Aerosolized medications such as dornase alfa and tobramycin have been associated with a lower incidence of massive hemoptysis and are recommended therapies for patients with advanced airways disease, yet they are also associated with a higher incidence of pneumothorax, which suggests careful assessment of their potential bronchospastic effect in patients with advanced airways disease. The respiratory therapist also plays a key role in the care of the patient with respiratory failure. Here is also discussed the role of ventilatory support and airway-clearance therapies in the patient with advanced stage disease. Now, more than ever, the patient needs caregivers with the knowledge and sensitivity to provide appropriate palliative care.

Family dynamics in families of severe COPD patients

The purpose of this study was to describe family dynamics in families with severe chronic obstructive pulmonary disease (COPD) on the basis of Barnhill's framework for healthy family systems. The sample consisted of 35 severe COPD patients and 30 family members at Tampere University Hospital, Finland or in the neighbouring regions. Chronic obstructive pulmonary disease is a public health problem worldwide. It is a slowly progressive airway disease, producing a decline in lung function which is not fully reversible. The sample included the families of patients without oxygen therapy and the families of patients who had long-term oxygen therapy (LTOT). The data were collected using the Family Dynamics Measure 2 (FDM2) and the Family Dynamics Questionnaire (FDQ). A quantitative research method was employed in the study. Frequency and percentage distributions, as well as cross-tabulations, were used to describe the data. Mean values and standard deviations were calculated for the sum variables of six dimensions of the FDM2. In the dimensions of individuation, mutuality and flexibility, dynamics in the families of patients with LTOT was significantly better than of the patients without oxygen therapy. Especially in the dimension of mutuality, the families of LTOT patients functioned very well, while in the dimensions of communication and roles, family dynamics in these families was notably worse, although still good. Poor self-identity--enmeshment, isolation from others and lack of flexibility to varying conditions--in families with severe COPD can weaken the ability of the families to manage in everyday life. Families need family nursing to adapt to alterations occurring when a family member has severe COPD. Nurses can give support and help for these families for their roles of patient and caregiver, as well as opportunities to speak with someone about their situation.

Radiological and functional changes over 3 years in young children with cystic fibrosis

The aim of the present study was to evaluate airway disease progression assessed by chest radiology, expiratory interrupter resistance (Rint,exp) and spirometry in young children with cystic fibrosis (CF) over a 3-yr period. Two chest radiographs combined with two R(int,exp) measurements were performed with a 3-yr interval in 21 preschool children (age (mean+/-sd) 3.2+/-0.9 yrs) and 30 schoolchildren with CF (age 7.2+/-1.9 yrs). Chest radiographs were scored using five different CF scoring systems and Rint,exp measurements were expressed as height-adjusted Z-scores. Spirometry was assessed in schoolchildren and the results were expressed as a percentage of predicted values. Chest radiograph scores worsened significantly over the 3-yr period and a tendency towards more pronounced changes was observed, especially for the Wisconsin score, in preschool children. Most preschool and schoolchildren had Rint,exp Z-scores within the normal range at start and follow-up, and the annual change in Rint,exp Z-score was not significant. In schoolchildren, only the forced expiratory volume in one second as a percentage of forced vital capacity declined significantly during the study period. In summary, in young children with cystic fibrosis, chest radiograph scores worsen significantly over time even while lung function remains stable.

Focusing on Global Environmental Health

From the problems of arsenic in drinking water, to indoor air pollution from burning of biomass as fuel, to lead’s effects in children, global environmental health problems are enormous and daunting. Some of these same or equally menacing hazards threaten the health of many in the United States, particularly and often disproportionately the poor; however, the scale of such threats here pales in comparison to that of much of the world. One irony of this situation is that the places where the environmental health crises seem most dire may offer the best opportunities for research toward understanding the problem and identifying solutions that ultimately improve world health. And we know, too, that when it comes to many environmental health problems, no one nation can stand in isolation; the action or inaction of those in one place has the potential to affect the lives of those far distant. We are currently engaged in a process of revitalizing and refocusing the NIEHS’s efforts in global environmental health to maximize our potential to prevent disease and improve human health. The NIEHS has a long history of partnering with universities and research institutes to support investigations into environmental health problems wherever they occur in the world. These partnerships have led to a better understanding of both the extent and mechanisms of problems such as arsenic in drinking water in Bangladesh, the link between aflatoxin and liver cancer in China, the effect of lead on children’s neurodevelopment in Mexico, and many others. The NIEHS is committed to its ongoing partnerships with the Fogarty International Center and other NIH institutes and centers as global issues in environmental health continue to emerge that potentially impact the American public. However, the successful development of new initiatives in global environmental health will require new partnerships, as well, partnerships that are equitable to all parties and based in mutual understanding, experiences, and commitment to addressing the scientific questions at hand. As a first step, we have started a new program that will offer funding to allow junior-level faculty scientists from developing nations to conduct research in NIEHS-funded laboratories. We are also exploring ways to support U.S.-based investigators to work in the laboratories of foreign scientists. The solutions to fundamental problems in environmental health require a global effort to better understand the causes and impact of these hazards on human health. The prevention of these diseases requires that we learn how to control exposures and identify those at risk of developing disease, as well as those in the early, reversible stage of illness. These advances will be facilitated in a collaborative research environment. Armed with this understanding, we believe the best approach for our program in global environmental health will be to focus our efforts on identifying a major problem in human health that is caused by a compelling environmental exposure—and thus is ultimately correctable—and working to address that problem through global partnerships. For example, childhood respiratory infections represent a preventable disease that causes substantial morbidity and mortality and is overrepresented in developing countries. The indoor burning of biomass fuels combined with outdoor air pollution very likely contributes to the deaths of children throughout the world each year from preventable respiratory infections and progressive airway disease. And although excess cardiovascular and pulmonary deaths have been linked to exposure to air pollution in many developed countries, we still don’t understand the fundamental pathogenesis of these diseases or why some individuals are more susceptible to these complications. Focusing on understanding childhood respiratory infections might create an opportunity to substantially enhance our understanding of all of these diseases and lead to measurable gains in human health in both the developing and developed world. This same scenario could likely prove true for many other environmental health problems as well, any of which may represent opportunities for the NIEHS to understand human biology and improve human health both here and abroad. In early 2007, we will be hosting a workshop to focus intensively on identifying global environmental health problems that may give us the greatest chance of better understanding human biology and improving human health in the not-too-distant future. We’re asking leaders in the environmental health sciences and other disciplines from around the world to help us pursue this question, as well as address the potential size and scope of the effort, the barriers to success, the methodologies that should be followed, and the possible partnerships that would facilitate an NIEHS-led effort. As global leaders in the environmental health sciences, we are obliged to understand how the environment contributes to inequities in world health and find lasting solutions to these problems.

Airway Inflammation and Bronchial Bacterial Colonization in Chronic Obstructive Pulmonary Disease

Inflammation is now recognized as an integral part of the pathogenesis of chronic obstructive pulmonary disease (COPD). In contrast to the sterile airways of normal lungs, bacterial pathogens are often isolated from the airways in stable COPD. This "colonization" of the tracheobronchial tree, currently believed to be innocuous, could serve as an inflammatory stimulus, independent of current tobacco smoke exposure. To test the hypothesis that bacterial colonization is associated with airway inflammation in stable COPD. Bronchoscopy with bronchoalveolar lavage (BAL) was performed in three groups of subjects: 26 ex-smokers with stable COPD (COPD), 20 ex-smokers without COPD (ex-smokers), and 15 healthy nonsmokers (nonsmokers). Quantitative bacterial cultures, cell counts, chemokine, cytokine, proteinase/antiproteinase, and endotoxin levels in the BAL fluid were compared. Potentially pathogenic bacteria were recovered at > or = 100 cfu/ml in 34.6% of COPD, 0% of ex-smokers, and in 6.7% of nonsmokers (p = 0.003). All values are expressed as median (interquartile range). Subjects with colonized COPD had significantly greater relative (12.0 [28.4] vs. 3.0 [7.8]%, p = 0.03) and absolute (4.98 [5.26] x 10(4)/ml vs. 3.04 [2.82] x 10(4)/ml, p = 0.02) neutrophil counts, interleukin 8 (33.8 [189.8] vs. 16.9 [20.1] pg/ml, p = 0.005), active matrix metalloproteinase-9 (2.16 [4.30] vs. 0.84 [0.99] U/ml, p = 0.03), and endotoxin (36.0 [72.6] vs. 3.55 [7.17] mEU/ml, p = 0.004) levels in the BAL than the subjects with noncolonized COPD. These inflammatory constituents of BAL were also significantly elevated in subjects with colonized COPD when compared with ex-smokers and nonsmokers. Bacterial colonization is associated with neutrophilic airway lumen inflammation in ex-smokers with COPD and could contribute to progression of airway disease in COPD.

AIRWAY INFECTION

Bronchitis in its acute and chronic forms with recurrent acute exacerbations is one of the most common reasons for physician visits, accounting for a significant cost to the health-care system, lost work days, and increased morbidity and mortality. Smoking and recurrent lower respiratory tract infections are major risk factors for chronic bronchitis. Therefore, smoking cessation and vaccination strategies are cornerstones of management in terms of halting disease progression and reducing the frequency of infectious exacerbations. Bacterial infection is the main culprit in acute flares of the disease. Routine antimicrobial therapy fails in a significant number of patients, and therapeutic failures lead to increased costs. Several stratification schemes have been proposed to improve initial antimicrobial selection. These schemes identify patient's age, severity of underlying pulmonary dysfunction, frequency of exacerbations, and the presence of comorbid illnesses as predictors for likely pathogens and to guide antimicrobial selection. This approach may reduce the risk for treatment failure, which would have significant medical and economic implications. Improved understanding of the roles of airway inflammation and infection in the pathogenesis of progressive airway disease, in addition to future studies examining the efficacy of newer classes of antimicrobials, should guide physicians to target early and effective treatment to high-risk patients.

Acute Effects of Herbal Tea Dust Extracts on Lung Function

The acute effect of herbal tea dust extracts on lung function was studied in 15 of 25 healthy subjects responding to the inhalation of these extracts. Bronchial inhalation challenge was performed with tea extracts (sage, dog rose and gruzyan) and with normal saline solution as a control substance to assess their baseline airway reactivity to an isotonic aerosol. Lung function testing was performed before exposure and at 0, 15, 30, and 60 minutes after the cessation of exposure. The same subjects were also tested by challenge with methacholine. Lung function was measured by recording FVC, FEV1, FEF50, FEF25, SGaw, and Raw. Subjects were skin tested by the skin prick method and serum IgE levels were determined. The findings suggested that neither baseline nonspecific airway reactivity nor specific markers of immediate sensitivity to tea predict airway responses to tea extracts. Further evaluation of immunologic markers may help to explain the onset and progression of airway disease in workers.