Current Respiratory Medicine Reviews - Volume 2, Issue 3, 2006

Bronchopulmonary Dysplasia (BPD) continues to be a major problem despite advances in the management of the sick preterm. Current evidence supports a multifactorial etiology to this disease. Prematurity is the cardinal factor; others include pulmonary baro/volu trauma, hyperoxia, and inflammation. A clearer understanding of genetic susceptibility for BPD has recently emerged. Twin studies have shown that 53% of the variance for BPD is genetic. This article will attempt to review the published literature appraising the relationship between single nucleotide polymorphisms of putative causal genes and susceptibility to BPD. These studies, though small in size, spark interest in further genetic association studies to identify candidate genes that contribute to the diverse pathophysiology of BPD.

Airways are protected from pathogens by forces allied with innate and adaptive immunity. Recent investigations establish critical defensive roles for leukocyte and mast cell serine-class peptidases garrisoned in membrane-bound organelles-here termed Granule-Associated Serine Peptidases of Immune Defense, or GASPIDs. Some better characterized GASPIDs include neutrophil elastase and cathepsin G (which defend against bacteria), proteinase-3 (targeted by antineutrophil antibodies in Wegener's vasculitis), mast cell β-tryptase and chymase (which promote allergic inflammation), granzymes A and B (which launch apoptosis pathways in infected host cells), and factor D (which activates complement's alternative pathway). GASPIDs can defend against pathogens but can harm host cells in the process, and therefore become targets for pharmaceutical inhibition. They vary widely in specificity, yet are phylogenetically similar. Mammalian speciation supported a remarkable flowering of these enzymes as they co-evolved with specialized immune cells, including mast cells, basophils, eosinophils, cytolytic T-cells, natural killer cells, neutrophils, macrophages and dendritic cells. Many GASPIDs continue to evolve rapidly, providing some of the most conspicuous examples of divergent protein evolution. Consequently, students of GASPIDs are rewarded not only with insights into their roles in lung immune defense but also with clues to the origins of cellular specialization in vertebrate immunity..

Small airway plays a major role in viral infection of the respiratory tract in infants and young children. Indeed these early viral infections have been shown to lead to airway remodeling and early development of non allergic asthma by affecting the expression of critical growth factors. In the old child and adult however, and until very recently, asthma has been considered largely a disease of the large airways. But as our understanding of asthma evolves, it now seems that the disease process in asthma is located in all parts of the tracheobronchial tree, small airways, and alveoli. Small airway remodeling has the potential to produce fixed airflow obstruction, which if untreated and unrecognized can lead chronic obstructive pulmonary disease. With the recognition of the important role of the small airways in the pathogenesis of asthma in infants as well as in adults, more aggressive modalities of treatment are urgently needed in order to have a positive impact on asthma outcome. This article will review the impact of early viral infections on airway remodeling in infants, the role that small airways play in older asthmatics, and finally the potential role of new HFA formulation for the treatment of asthma.

Ventilator associated pneumonia remains a cause of significant morbidity and mortality in Intensive Care patients despite advances in knowledge and technology. The presence of an endotracheal tube bypassing the normal airway barriers, oropharyngeal bacterial colonisation, patient position and repetitive micro-aspiration tip the host-pathogen relationship in favour of the pathogen and promote lung infection in a time-dependent manner. Defending the lung against microbial invasion and infection is a multiplicity of innate and adaptive immune mechanisms, which can identify and eliminate potential pathogens. These defence mechanisms include the ability to recognise pathogens through cell-surface receptors, antimicrobial peptides and proteins, pro and anti-inflammatory mediators and factors related to the coagulant state of the lung fluid. The mechanisms are characterised by their complexity, their remarkable degree of redundancy and effectiveness.

Chronic obstructive pulmonary disease (COPD) is a common, complex disorder, and dissection of its individual components is considered one of the research priorities for this disease. Several lines of evidence suggest that, in spite of the massive role of cigarette smoking, common COPD is not just an environmental phenocopy of COPD associated with alpha1-antitrypsin deficiency: from the racial/ethnic variability in COPD prevalence to the individual susceptibility to cigarette smoke, from the familial aggregation of lung function levels to the familial clustering of COPD symptoms, all lines tend to point to common COPD having a genetic component. The challenge in the last three decades has been to define the borders of this component, its relative weight with respect to the environmental component, and to identify the susceptibility and/or resistance genes. Taking advantage from the knowledge, albeit limited, of the biochemical basis of COPD, a number of genetic polymorphisms have been investigated, mostly in case-control association studies. Although such a strategy is considered more successful than linkage analysis for investigating complex, non-Mendelian disorders and in spite of the considerable amount of data collected, the overall result of the genetic investigations into COPD has so far been largely disappointing. A critical evaluation of the published reports shows that a number of issues could have affected the outcome of the investigations: among such issues, the choice of the appropriate clinical phenotype is fundamental.

Pleural diseases are a commonly encountered problem by general physicians and chest specialists alike. Despite this, there has been a lack of research over the last few decades in this important field. This review focuses on new developments in the management of pleural effusions. We have restricted our attention, in the main, to randomised controlled trials. The review is evidence-based with practical suggestions from the authors to practicing clinicians. Specific areas focused on are pleural infection and malignant pleural disease. In pleural infection, the importance of pleural pH is emphasised and we have incorporated the latest evidence on the use of fibrinolytics from the recent multi-centre randomised controlled MIST trial. In malignant pleural effusion, the best way of obtaining closed pleural biopsy is discussed. With regard to pleurodesis, recent data on the importance of knowing your talc particle size is highlighted, as well as the role of fibrinolytics, thoracoscopy and when to use Pleurx catheters. Finally, the latest developments on newer diagnostic markers such as mesothelin in mesothelioma and newer anti-pleural agents such as transforming growth factor-beta (TGF-β) and vascular endothelial growth factor (VEGF) antagonists have been reviewed.

Exposure to hyperoxia (> 95% O2) is a necessary therapeutic treatment used to maintain tissue oxygenation in patients with compromised lung function and decreased pulmonary gas exchange. Hyperoxia causes increased formation of reactive oxygen species (ROS), which accumulate in the cells of the lung resulting in cell death and compromised tissue function. Recent observations have demonstrated that different lung cell types respond differently to increased oxidative stress raising many questions about the cell-type restricted response of different pulmonary cell types. This review will focus on three main aspects of chronic oxidative stress in a cell-type specific manner: the role of antioxidant defenses, DNA repair, and apoptotic signaling.

Pulse oximetry is commonly used in clinical practice as an indirect monitor of blood oxygen saturation. There are many factors, however, that can interfere with accurate readings. We present a case of a woman with metastatic thyroid cancer that had a sudden drop in her pulse oximetry during bronchoscopy and that eventually was found to have an uncommon cause for a misleading persistently low oxygen saturation.

For decades, neurologic and pulmonary disorders have been associated to diabetes mellitus (DM) and more recently to obesity. Many studies have attempted to establish the association between sleep apnea and adult-onset DM. Growing evidence exists demonstrating the association between insulin-resistance and obstructive sleep apnea (OSA), as well as sleep-disordered breathing (SDB) in non-obese diabetic patients with autonomic neuropathy. In patients with DM, two types of sleep disorders can be found; upper airway resistance syndrome and sleep apnea. The later apnea can be central, obstructive or mixed. In either case, a decrease in the oxygen saturation will ensue, and sleep arousal will occur. The diagnosis of sleep apnea in patients with DM is mainly done by obtaining a good history and physical examination. The main symptoms in the patient with sleep apnea include excessive daytime sleepiness (frequently seen in situations which are not mentally demanding). Effective continued positive airway pressure (CPAP) treatment show clinical improvement in symptoms as well as in insulin sensitivity. The relation between SDB and DM can have significant impact on the overall health of the patient.

Thickening of the basement membrane zone (BMZ) is a characteristic feature of airway remodeling. The BMZ appears as three component layers: the laminas lucida, densa, and reticularis. The lamina reticularis of the BMZ is thickened in asthma, allergic rhinitis, eosinophil bronchitis and lung transplants. Collagen types I, III and V form heterogeneous fibers that account for the thickness of the BMZ. Proteoglycans are structural component of the BMZ responsible for many of its functions, in particular, trafficking of growth factors and cytokines between epithelial and mesenchymal cells. An important function of the BMZ is storage and regulation of fibroblast growth factor-2 (FGF-2). FGF-2 has been shown to be involved with normal growth and thickening of the BMZ. Treatment with corticosteroids reduces the width of the BMZ in asthmatics. The significance of BMZ thickening in airway function is not clear however, it may have a positive effect by physically protecting against airway narrowing and air trapping. Thickening of the BMZ may have a negative effect by influencing how the epithelial mesenchymal trophic unit functions. However at this point there are no studies showing abnormal trafficking of growth factors and cytokines due to thickening of the BMZ.

The selectin family of cell adhesion molecules (selectins) is comprised of three structurally related calciumdependent carbohydrate binding proteins, E-, P-, and L-selectin. Located on the surface of endothelial cells (E- and Pselectin), platelets (P-selectin) and of leucocytes (L-selectin), selectins are of vital importance for leukocyte recruitment and accumulation in the vasculature. Based on the unique architecture of the microvasculature of the lung, this task is achieved by two different types of selectin mediated functions (i) tethering and rolling of leukocytes on the pre- and post capillary pulmonary endothelium and in bronchial venules which are mediated by E-, P-, and L-selectin as well as (ii) retention of leukocytes in the pulmonary capillaries by L-selectin. Recent findings in preclinical and clinical research suggest a significant involvement of selectins in both acute and chronic inflammatory lung diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), asthma bronchiale (Asthma), chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). This review summarizes the current progress in understanding the role of selectins during inflammation in the lung and its potential impact for innovative therapeutic strategies.