Primary Airways Research Articles

Pathology of small airways disease.

N Context.—The term small airways disease encompasses a generally poorly understood group of lung diseases that may arise primarily within the small airways or secondarily from diseases primarily affecting the bronchi or lung parenchyma. Their histology may be confusing; however, because treatments and prognoses vary, correct pathologic diagnosis is important. Objective.—To present a nonexhaustive review of the pathology of primary and secondary small airways diseases, including small airways disease related to tobacco; to various other exposures, including mineral dusts; to diseases involving other areas of the lung with secondary bronchiolar involvement; and to recently described bronchiolitic disorders. Data Sources.—Current literature is reviewed. Conclusions.—Small airways diseases include a wide variety of diseases of which the pathologist must consider. Uncommon conditions such as diffuse idiopathic neuroendocrine cell hyperplasia and diffuse panbronchiolitis may show relatively specific diagnostic features histologically; however, most small airways diseases exhibit nonspecific histologic features. Conditions not considered primary pulmonary diseases, such as collagen vascular diseases, bone marrow transplantation, and inflammatory bowel disease, must also be considered in patients with small airways changes histologically. Clinical and radiologic correlation is important for obtaining the best possible diagnosis. (Arch Pathol Lab Med. 2010;134:702–718)

Pathology of Small Airways Disease

The term small airways disease encompasses a generally poorly understood group of lung diseases that may arise primarily within the small airways or secondarily from diseases primarily affecting the bronchi or lung parenchyma. Their histology may be confusing; however, because treatments and prognoses vary, correct pathologic diagnosis is important. To present a nonexhaustive review of the pathology of primary and secondary small airways diseases, including small airways disease related to tobacco; to various other exposures, including mineral dusts; to diseases involving other areas of the lung with secondary bronchiolar involvement; and to recently described bronchiolitic disorders. Current literature is reviewed. Small airways diseases include a wide variety of diseases of which the pathologist must consider. Uncommon conditions such as diffuse idiopathic neuroendocrine cell hyperplasia and diffuse panbronchiolitis may show relatively specific diagnostic features histologically; however, most small airways diseases exhibit nonspecific histologic features. Conditions not considered primary pulmonary diseases, such as collagen vascular diseases, bone marrow transplantation, and inflammatory bowel disease, must also be considered in patients with small airways changes histologically. Clinical and radiologic correlation is important for obtaining the best possible diagnosis.

Health burden of co-morbid asthma and allergic rhinitis in West Indian children

Co-morbid allergic rhinitis (AR) and asthma has not been studied in Caribbean countries where there is a high prevalence of childhood asthma. Using the International Primary Care Airways Group (IPAG) guidelines to determine AR, care-givers of 393 (response rate=100%) children attending asthma clinics in selected public sector health facilities in Trinidad, West Indies, were interviewed. Children (393) were between 2-17 years and included 239 (60.8%) boys and 154 (39.2%) girls. As many as 53.9% of children sampled (95% CI 45.9-55.8) suffered from AR. Children exposed to household smoking were nearly twice as likely to have AR (p<0.0041, OR=1.9, CI 1.22-2.88). Significantly (p<0.01) more asthmatics with AR (154, 58.6%) visited Accident and Emergency (A&E) in the past 12 months. The odds of visiting A&E at least once in the past 12 months for asthmatics with AR were 1.75 (95% CI 1.15-2.68). The average frequency of A&E visits was higher in children who also suffered from AR (1.75 vs 1.36, p<0.04). Age was negatively correlated (-0.21, p<0.005) with exacerbation frequency for asthmatics without AR suggesting A&E visits are independent of age in co-morbid disease. More children with AR (>60%) suffer day and night symptoms (p<0.001), and miss school (59.8%) (p<0.03) at least once a week (p<0.002) than asthmatics without AR (OR=1.5, 95% CI=1.03-2.30). AR is prevalent in 53.9% of Trinidadian children with asthma. The burden of co-morbid disease in asthmatic children is associated with increased likelihood of asthma-related A&E visits, day and night symptoms and absence from school.

Prevalence of asthmatic symptoms in Lebanese patients with type 1 diabetes and their unaffected siblings compared to age-matched controls

Patients with type 1 diabetes (a TH1 disease) have been reported to be at a lower risk of developing asthma (a TH2 disease). Both diseases are affected by environmental and genetic factors. Our objective is to examine this relationship in Lebanon, a Middle-Eastern country, where no previous similar studies are available. This is a cross-sectional observational study conducted at the Chronic Care Center, a referral medical center for type 1 diabetics. Patients with type 1 diabetes aged 6-39 years old, their unaffected siblings and age-matched control completed the International Primary Care Airways Group asthma screening questionnaire. The prevalence of asthma symptoms was compared among the three groups and separately within a subgroup of diabetics in relation to their carrier state of previously collected genetic data. Among 305 diabetics, 776 siblings and 187 controls, diabetics were at lower risk of having any asthma symptoms than controls; OR 0.48 (95% CI 0.32-0.72, p < 0.001) and siblings were at lower risk than diabetics and controls; OR 0.64 (95% CI 0.45-0.91, p = 0.01) and 0.28 (95% CI 0.19-0.42, p < 0.001), respectively. Among 66 diabetics, carriers of the HLA-DQB1*0201 allele were at lower risk of having any asthma symptoms than non-carriers (25.5 vs. 53.3%, p = 0.04). Only a statistically non-significant trend of higher risk was observed in carriers of HLA-DQB1*0301 and G allele at the 49 (A/G) nucleotide of CTLA-4 gene. The TH1-TH2 paradigm might partially explain these findings, since siblings were the least to report asthma symptoms. Future research is needed with diagnostic tests for asthma and extensive genetic testing.

Allergic rhinitis management pocket reference 2008*

Allergic rhinitis is a major chronic respiratory disease because of its prevalence, impacts on quality of life and work/school performance, economic burden, and links with asthma. Family doctors (also known as 'primary care physicians' or 'general practitioners') play a major role in the management of allergic rhinitis as they make the diagnosis, start the treatment, give the relevant information, and monitor most of the patients. Disease management that follows evidence-based practice guidelines yields better patient results, but such guidelines are often complicated and may recommend the use of resources not available in the family practice setting. A joint expert panel of the World Organization of Family Doctors (Wonca), the International Primary Care Airways Group (IPAG) and the International Primary Care Respiratory Group (IPCRG), offers support to family doctors worldwide by distilling the globally accepted, evidence-based recommendations from the Allergic Rhinitis and its Impact on Asthma (ARIA) initiative into this brief reference guide. This guide provides tools intended to supplement a thorough history taking and the clinician's professional judgment in order to provide the best possible care for patients with allergic rhinitis. A diagnostic Questionnaire specifically focuses the physician's attention on key symptoms and markers of the disease. When questionnaire responses suggest a diagnosis of allergic rhinitis, a Diagnosis Guide and a simple flowchart then lead the clinician through a series of investigations commonly available in primary care to support the diagnosis. In addition, key aspects of differential diagnosis are illuminated. According to ARIA, allergic rhinitis may be classified as Intermittent or Persistent, and as Mild or Moderate/Severe. The classification of rhinitis determines the treatment necessary, as set out in an ARIA flowchart included in this guide. The guide also includes information about the strength of evidence for efficacy of certain rhinitis treatments, a brief discussion of pediatric aspects, and a glossary of allergic rhinitis medications to assist the clinician in making medication choices for each individual patient. Finally, many patients with allergic rhinitis also have concomitant asthma, and this must be checked. The World Organization of Family Doctors has been delegated by WHO as the group that will be taking primary responsibility for education about chronic respiratory diseases among primary care physicians globally. This document will be a major resource in this educational program.

Asthma management pocket reference 2008*

Asthma is one of the most common chronic airways diseases worldwide, and its prevalence is increasing. Family doctors (sometimes called 'primary care physicians' or 'general practitioners') are frequently an asthma patient's first point of contact with healthcare systems. Disease management that follows evidence-based practice guidelines yields better patient results, but such guidelines are often complicated and may recommend the use of resources not available in the family practice setting. A joint expert panel of the World Organization of Family Doctors (Wonca), International Primary Care Airways Group (IPAG) and the International Primary Care Respiratory Group (IPCRG) offers support to family doctors worldwide by distilling the globally accepted, evidence-based recommendations from the Global Initiative for Asthma (GINA) into this brief reference guide. This guide provides tools intended to supplement a thorough history taking and the clinician's professional judgment in order to provide the best possible care for patients with asthma. Diagnostic Questionnaires developed for children and adults specifically focus the physician's attention on key symptoms and markers of asthma. When questionnaire responses suggest a diagnosis of asthma, Diagnosis Guides then lead the clinician through a series of investigations commonly available in primary care to support the diagnosis. In patients >40 years who smoke, COPD is an important alternative diagnosis, and some key aspects of differential diagnosis are illuminated. According to GINA, the goal of asthma treatment is to achieve and maintain control of the disease symptoms long-term. The physician must first assess the patient's current level of asthma control, then treat asthma in a stepwise manner to achieve and maintain symptom control. Both of these aspects are summarized in figures included in this guide. Finally, the guide also presents a flow chart summarizing management of asthma exacerbations in the acute care setting, and a glossary of asthma medications to assist the clinician in making medication choices for each individual patient. Finally, many patients with asthma also have concomitant allergic rhinitis, and this must be checked. The World Organization of Family Doctors has been delegated by WHO as the group that will be taking primary responsibility for education about chronic respiratory diseases among primary care physicians globally. This document will be a major resource in this educational program.

Physiologic similarities and differences between asthma and chronic obstructive pulmonary disease

This review examines the physiologic mechanisms responsible for persistent maximum expiratory airflow limitation in nonsmoking patients with acute and chronic moderate to severe persistent asthma in comparison to chronic obstructive pulmonary disease. The phenomenon of acute but reversible loss of lung elastic recoil during acute asthma is reviewed, although no plausible pathophysiologic explanation has been offered. Nonsmoking adults with stable asthma and persistent maximum expiratory airflow limitation, despite optimal polytherapy, were shown to have unsuspected and unexplained marked loss of lung elastic recoil in the absence of lung computed tomography scored emphysema. This condition resulted in up to 50% reduction in maximum expiratory airflow. Furthermore, these patients remain at high risk for adverse clinical events, including near-fatal asthma. In chronic obstructive pulmonary disease, reduction in maximum expiratory airflow is related to variable extent of loss of lung elastic recoil secondary to emphysema and concurrent intrinsic airway obstruction or obliteration of small airways. There is also an unexplained loss of lung elastic recoil in primary intrinsic small airways disease in the absence of emphysema. Nonsmoking patients with moderate-severe persistent asthma and patients with smoking-related chronic obstructive pulmonary disease share similar physiologic mechanisms of expiratory airflow limitation, but probably caused by different anatomic abnormalities.

Primary care and palliative care

Over the past decade, interest in diagnosing and managing COPD in primary care has grown in recognition of its increasing burden on patients, families, health services, and society. Guidelines from...

Validation of the Anti-Inflammatory Properties of Small-Molecule IκB Kinase (IKK)-2 Inhibitors by Comparison with Adenoviral-Mediated Delivery of Dominant-Negative IKK1 and IKK2 in Human Airways Smooth Muscle

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airway inflammation. However, because patients with COPD and certain patients with asthma show little or no therapeutic benefit from existing corticosteroid therapies, there is an urgent need for novel anti-inflammatory strategies. The transcription factor nuclear factor-kappaB (NF-kappaB) is central to inflammation and is necessary for the expression of numerous inflammatory genes. Proinflammatory cytokines, including interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, activate the IkappaB kinase complex (IKK) to promote the degradation of inhibitory IkappaB proteins and activate NF-kappaB. This pathway and, in particular, the main IkappaB kinase, IKK2, are now considered prime targets for novel anti-inflammatory drugs. Therefore, we have used adenoviral overexpression to demonstrate NF-kappaB and IKK2 dependence of key inflammatory genes, including intercellular adhesion molecule (ICAM)-1, cyclooxygenase-2, IL-6, IL-8, granulocyte macrophage-colony-stimulating factor (GM-CSF), regulated on activation normal T cell expressed and secreted (RANTES), monocyte chemotactic protein-1 (MCP-1), growth-regulated oncogene-alpha (GROalpha), neutrophil-activating protein-2 (NAP-2), and epithelial neutrophil activating peptide 78 (ENA-78) in primary human airways smooth muscle cells. Because this cell type is central to the pathogenesis of airway inflammatory diseases, these data predict a beneficial effect of IKK2 inhibition. These validated outputs were therefore used to evaluate the novel IKK inhibitors N-(6-chloro-9H-beta-carbolin-8-yl) nicotinamide (PS-1145) and N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methyl-nicotinamide (ML120B) on IL-1beta and TNFalpha-induced expression, and this was compared with the corticosteroid dexamethasone. As observed above, ICAM-1, IL-6, IL-8, GM-CSF, RANTES, MCP-1, GROalpha, NAP-2, and ENA-78 expression was reduced by the IKK inhibitors. Furthermore, this inhibition was either as effective, or for ICAM-1, MCP-1, GROalpha, and NAP-2, more effective, than a maximally effective concentration of dexamethasone. We therefore suggest that IKK inhibitors may be of considerable benefit in inflammatory airways diseases, particularly in COPD or severe asthma, in which corticosteroids are ineffective.

International Primary Care Respiratory Group (IPCRG) Guidelines: Dissemination and Implementation — a proposed course of action

There is growing evidence that good implementation of evidence-based guidelines can result in improvement in health outcomes. This paper on Dissemination and Implementation constitutes the final paper of the IPCRG Guidelines on the management of chronic respiratory diseases in primary care. It highlights the historical development of these guidelines following the formation of the International Primary Care Airways Group (IPAG) in 2001 together with its dissemination and implementation subgroup, and the subsequent transfer of this dissemination and implementation role to the IPCRG. It covers the main factors within the IPCRG workplan, including the issues of governance, launch, dissemination, implementation, and evaluation.

The Splicing and Fate of ADAM33 Transcripts in Primary Human Airways Fibroblasts

The ADAM (A Disintegrin and Metalloprotease) family of Zn++-dependent metalloproteases are multidomain proteins involved in diverse cellular activities. Polymorphic variation in ADAM33 is strongly associated with asthma and bronchial hyperresponsiveness. Identification of those isoforms of ADAM33 that are expressed in airways is fundamental to dissecting the role of ADAM33 in asthma. Analysis of primary human airways fibroblasts has shown the presence of a number of alternatively spliced forms of ADAM33, including one encoding a putative secreted variant, and many transcripts lacking the metalloproteinase domain. The relative abundance of these transcripts has been quantified using reverse transcription real-time polymerase chain reaction, in both nuclear and cytoplasmic fractions of RNA. These results demonstrate that a number of splice variants of ADAM33 are transported into the cytoplasm. Ninety percent of ADAM33 mRNA is retained in the nucleus and the subtle differences in the composition of nuclear and cytoplasmic RNA suggest important events in the splicing and selection of ADAM33 transcripts. Western blot analysis confirmed that several protein isoforms of ADAM33 are expressed in primary airways fibroblasts. These findings demonstrate that ADAM33 exists in multiple isoforms, suggesting that it is a complex molecule that plays multiple roles within mesenchymal cells.

Nasal allergy and atmospheric pollution

Among the effects that pollution of the air causes on human health, irritation of the exposed mucosa is the earliest and the most obvious one. Pollutants damage the anatomical and functional integrity of the primary airways, in particular they cause alteration of the mucociliary system. The mucosa undergoing continuous aggression by an aerosol loaded with pollutants assumes the characteristics of a tissue with chronic inflammatory processes with dysepithelialised areas that could be an easy entrance for airborne allergens. The loss of integrity of epithelial lining, the interference with the repulsion of extraneous particles trapped in the mucus, the infiltration of the inflammatory cells and lymphocytes called into action by the phlogistic reaction multiply the occasion of meeting between environmental allergens and the immunological system of the host and basically of setting in motion the process of sensitisation. So there is a strict relationship between nasal allergy and pollution, that should not be ignored: allergy is the cause of considerable disturbances interfering with study, work and social activity and can lead to local and distal complications.

Sonic hedgehog regulates branching morphogenesis in the mammalian lung.

The mammalian lung, like many other organs, develops by branching morphogenesis of an epithelium [1]. Development initiates with evagination of two ventral buds of foregut endoderm into the underlying splanchnic mesoderm. As the buds extend, they send out lateral branches at precise, invariant positions, establishing the primary airways and the lobes of each lung. Dichotomous branching leads to further extension of the airways. Grafting studies have demonstrated the importance of bronchial mesenchyme in inducing epithelial branching, but the significance of epithelial signaling has largely been unstudied. The morphogen Sonic hedgehog (Shh) is widely expressed in the foregut endoderm and is specifically upregulated in the distal epithelium of the lung where branching is occurring [2]. Ectopic expression of Shh disrupts branching and increases proliferation, suggesting that local Shh signaling regulates lung development [2]. We report here that Shh is essential for development of the respiratory system. In Shh null mutants, we found that the trachea and esophagus do not separate properly and the lungs form a rudimentary sac due to failure of branching and growth after formation of the primary lung buds. Interestingly, normal proximo-distal differentiation of the airway epithelium occurred, indicating that Shh is not needed for differentiation events. In addition, the transcription of several mesenchymally expressed downstream targets of Shh is abolished. These results highlight the importance of epithelially derived Shh in regulating branching morphogenesis of the lung.

Influence of epidermal growth factor and transforming growth factor beta-1 on patterns of fetal mouse lung branching morphogenesis in organ culture.

Transforming growth factor-beta (TGF-beta), a potent inhibitor of epithelial cell proliferation, and epidermal growth factor (EGF), a mitogenic polypeptide that binds to cell surface receptors, are important regulators of cell differentiation; however, their distinct role(s) in lung development and their mechanisms of action are not well understood. We evaluated the effects of these factors on lung morphogenesis in murine fetal lungs at gestational day 14 (time:zero) and again after 7 days in culture. Baseline controls were cultured after tracheal transection in supplemented BGJb medium, and other tracheally transected lungs were cultured following addition of EGF (10 ng/ml BGJb), TGF-beta1 (2 ng/ml BFJb), or with both in combination added to the medium. The control lungs in culture had poorly developed airways and an absence of defined acinar structures. The addition of EGF resulted in hyperplasia of primary airways with stunted outgrowths, monopodial branching, and absence of distinct acinar structures. Addition of TGF-beta1 alone, led to significant elongation of primary airways, without normal airway branching; however, terminal dipodial branching was seen and the prospective pulmonary acini were well defined. Combination of these growth factors (GF) resulted in a more normal branching pattern and differentiation, suggesting their epigenetic role in lung morphogenesis and mutual interactive mechanisms that regulate lung development. These lungs had more abundant and larger lamellar bodies than those after other treatments. Control lungs remained immature with prominent glycogen aggregates with occasional dense lamellar bodies. The total protein and DNA contents were highest with EGF treatment, followed by combination treatment; these observations were supported by immunohistochemical localization of proliferating cell nuclear antigen, an indication of the proliferative state of tissues. All the surfactant proteins were relatively unaltered and their messages were up-regulated for SP-A, but down-regulated for SP-B and SP-C in the lungs treated with growth factors. In conclusion, we have demonstrated enhanced biochemical and structural development of lungs treated in vitro with GF, and propose that further research in this area may lead to therapeutic uses of GF alone or in combination with other agents for the treatment of newborn respiratory distress due to lung immaturity or hypoplastic lung development.

Lipopolysaccharide Induces Expression of Granulocyte/Macrophage Colony-stimulating Factor, Interleukin-8, and Interleukin-6 in Human Nasal, but Not Lung, Fibroblasts: Evidence for Heterogeneity within the Respiratory Tract

Fibroblasts play an indirect augmenting effector role in the inflammatory response by releasing growth and differentiation factors and other inflammatory mediators after activation by inflammatory cytokines such as interleukin (IL)-1, but whether direct activation occurs by exogenous agents such as endotoxin (lipopolysaccharide, LPS) remains controversial. Using a number of primary human airways tissue-derived fibroblast lines, we demonstrate that in contrast to IL-1 alpha, LPS significantly induced gene expression and production of granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-8, and IL-6 only in nasal but not bronchial or lung tissue-derived fibroblasts. Enhanced expression was dose- and time-dependent, and the minimal stimulatory dose was 10 ng LPS/ml. Polymyxin B entirely abrogated increased cytokine expression by LPS. Actinomycin D treatment largely inhibited expression, and LPS markedly increased an IL-6 gene promoter-driven luciferase reporter response in transfected nasal fibroblasts, suggesting enhanced expression may involve transcriptional regulation. Secondary protein or IL-1 synthesis requirement seemed unlikely since cycloheximide superinduced LPS-stimulated cytokine expression and anti-IL-1 alpha/beta antibodies failed to abrogate the response. Thus our data show that GM-CSF, IL-8, and IL-6 are directly inducible in nasal fibroblasts by LPS, and establish heterogeneous responsiveness to LPS by different fibroblast populations in the airways.

Comparison of Direct Fick and Thermodilution Measurements of Cardiac Output in Primary Pulmonary Hypertension and Chronic Obstructive Airways Disease

Comparison of Direct Fick and Thermodilution Measurements of Cardiac Output in Primary Pulmonary Hypertension and Chronic Obstructive Airways Disease