Current Respiratory Medicine Reviews - Volume 8, Issue 2, 2012

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The purpose of this article is double, to review the mechanisms allowing to control the volume of the extravascular lung water and then to trace a pathophysiological basis for the development of lung edema when such control is lost. Efficient gas diffusion in the air-blood barrier is guaranteed by an extremely low volume of extravascular water, assuring a minimum barrier thickness, and by a perfect matching between alveolar perfusion and ventilation. Low microvascular permeability and dynamic remodeling of the interstitial matrix and of microvessels maintain this equilibrium. Lung cells play a crucial role by acting as early sensors of the dysregulation of lung water balance. When capillary filtration increases due to an increase in microvascular permeability (e.g as in hypoxia), interstitial pressure rises substantially due to the rigidity of the interstitial compartment. This triggers mechano-transduction in lung cells through the expression of lipid microdomains that represent specific signaling platforms. Severe edema occurs as a result of yielding/fragmentation of important link proteins (matrix proteoglycans) to excessive tissue stress. The reparative matrix remodeling is stimulated by FGFβ (Fibroblast Growth Factor β ) and KGF (Keratinocyte Growth Factor). In edematous regions the increase in tissue pressure may cause compression of microvessels and associated marked precapillary vasoconstriction, thus resulting in an increase in pulmonary vascular resistances. Vascular remodeling decreases blood flow in edematous regions and favors blood redistribution to normal regions. Pulmonary hypertension is common to all conditions of severe lung edema and is proportional to the extension of the edematous process. In conclusion, it appears tempting to think of pulmonary hypertension as the consequence, rather than the cause, of lung edema which would lead to hypothesize that an excessive fibro-proliferative process in the lung might be interpreted as the response to a chronic condition of high microvascular permeability.

The literature data confirm that membrane rafts are required for the proper organization of signalling pathway within lung parenchyma. The physiological role of membrane rafts appears to be closely linked to their ability to modulate contraction, cell proliferation, matrix protein and mediator production by airway mesenchymal and airway/alveolar epithelial cells. In particular, the data obtained in endothelial cells suggest that in membrane rafts signalling complexes are assembled allowing a rapid, efficient and regulated response to extracellular stimuli. In fact, the presence of caveolae and Cav-1 is required in endothelial cells for short and long term mechano-transduction in blood vessels. The endothelium lacking caveolae is unable to couple changes in blood flow with proportional vascular remodeling, suggesting that caveolae might represent an initial flow mechano-sensor directly regulated by luminal blood flow. It is evident that membrane rafts, particularly caveolae, play critical roles in several cell types present in the lung and the aberrant regulation of caveolin expression may trigger pulmonary defects, including pulmonary hypertension, inflammation and fibrosis. A better understanding of dynamics of caveolae in transmembrane traffic in the lung might be of specific interest in drug targeting delivery.

This review summarizes recent research on biomarkers of tissue remodeling in different body fluids of patients suffering with pulmonary diseases. In particular we focus on elastin breakdown products, matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in syndromes such as chronic obstructive pulmonary disease, pulmonary hypertension, acute lung injury/acute respiratory distress syndrome and cystic fibrosis. Data from both preclinical disease models as well as clinical evaluation of the aforementioned biomarkers will be examined.

Ventilator-induced lung injury (VILI) is recognized as a hospital-acquired condition and significant source of morbidity and mortality in patients exposed to mechanical ventilation at injurious settings. Wounded lung cells are important transducers of injurious stress, and through the process of mechanotransduction the physical and chemical signals emitted from these cells lead to the deleterious sequelae of acute lung injury. Low tidal volume (VT) ventilation strategies have improved outcomes by minimizing deforming stress and associated lung injury, yet the mechanisms surrounding the inciting mechanotransduction event, the mechanical wounding and disruption of the alveolar epithelium, remain poorly characterized. Regional variation in lung mechanics due to preexisting disease, acute pathological processes, prestress of the parenchyma by gravity, and the selection of ventilator settings, influence the topographical distribution of VT and deformation experienced by constituent lung cells. In this short review we explore the mechanical effects of VT on deformation and stress experienced by airway constituent cells, and outline two distinct mechanisms of alveolar cell injury by deforming stress: Overdistension and interfacial injury. The general cytoskeletal polymerization state and associated load-bearing elements (actin anchoring proteins, cell-cell junctions, and focal adhesions) contribute biophysical determinants of injury common to both mechanisms and ought be explored for potential therapeutic applications. Nonetheless these mechanisms are unique and evidence suggests that cytoprotective interventions targeting interfacial injury are not likely to protect against overdistension or vice versa. Such complexity may account for some of the variable success with ‘ lung protective strategies’ at the bedside.

Here we provide background information for the pathobiological concept of a “sick lung circulation”, and how it may affect cardiac function. We propose that in most chronic and progressive lung diseases, but in particular COPD/emphysema and interstitial lung diseases (ILD), there are significant pathological changes of the small pulmonary vessels. Complementing the WHO classification of pulmonary vascular diseases we provide a classification which is based on pathogenetic mechanisms such as inflammation, hypoxia and angioproliferation. We also propose that chronic lung disease – related ‘ cor pulmonale’ is insufficiently explained by an elevation of the pulmonary arterial pressure.

High altitude constitutes an exciting natural laboratory for medical research. Over the past decade, high-altitude studies have provided important new insight into the regulation of the pulmonary circulation. Studies in high-altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide for pulmonary artery pressure homeostasis. Studies of healthy and maladapted high-altitude dwellers have provide important new insight into mechanisms conferring protection against/predisposing to pulmonary hypertension. Finally, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary (and systemic) vascular dysfunction at an early stage. Here, we will summarize recent studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning pulmonary hypertension and to the first direct demonstration of fetal programming of pulmonary vascular dysfunction in humans.

Respiratory irregularities normally occur during sleep. In populations afflicted with obstructive sleep apnea (OSA) or chronic pulmonary disease (COPD), these breathing irregularities become more pronounced and subsequently lead to adverse effects on health. Overlap syndrome (OS) is defined as the co-existence of COPD and OSA in the same patient. Patients with overlap syndrome have a worse prognosis compared to those with either COPD or OSA alone. The purpose of this report is to describe the pathophysiology of COPD and OSA, as each disease process contributes uniquely to the development of OS. We also describe the epidemiology, clinical presentation, diagnosis, prognosis, and treatment of OS. The diagnosis of OS is challenging due to variable clinical presentations. Symptoms such as fatigue, are subtle and non-specific; therefore, clinicians should have a high index of suspicion for diagnosis. Diagnostic tools include pulmonary function tests to confirm chronic obstruction as well as polysomnography to evaluate breathing patterns during sleep. Presence of apneas and hypopneas associated with concomitant arousals and hypoxia, contribute to the diagnosis of sleep apnea in COPD patients. Clinicians should treat overlap syndrome by optimizing bronchodilator therapy for COPD and administering continuous positive airway pressure with or without supplemental oxygen during sleep. Prompt diagnosis and treatment benefits the patient not only by providing practical relief from symptoms such as daytime fatigue; more importantly, treatment of OS significantly impacts health by helping to reduce cardiovascular complications.

Depression and anxiety are highly comorbid with chronic obstructive pulmonary disease (COPD) and are associated with poor treatment adherence, increased rates of physical disability, functional disability, mortality, healthcare costs, and a worsening quality of life. Despite its prevalence, there is a dearth of research on psychological treatments for depressed and/or anxious patients with COPD. This review examines the current evidence for psychological treatments for depression and anxiety in COPD, structured within the RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework, in an effort to highlight the current practice and research needs for this important and complex patient population.