Sharon Rounds

Combined Pulmonary Fibrosis and Emphysema Syndrome: A Review

There is increasing clinical, radiologic, and pathologic recognition of the coexistence of emphysema and pulmonary fibrosis in the same patient, resulting in a clinical syndrome known as combined pulmonary fibrosis and emphysema (CPFE) that is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis, and abnormalities of gas exchange. This syndrome frequently is complicated by pulmonary hypertension, acute lung injury, and lung cancer. The CPFE syndrome typically occurs in male smokers, and the mortality associated with this condition, especially if pulmonary hypertension is present, is significant. In this review, we explore the current state of the literature and discuss etiologic factors and clinical characteristics of the CPFE syndrome.

Recent Advances In Chest MedicineCombined Pulmonary Fibrosis and Emphysema Syndrome: A Review

There is increasing clinical, radiologic, and pathologic recognition of the coexistence of emphysema and pulmonary fibrosis in the same patient, resulting in a clinical syndrome known as combined pulmonary fibrosis and emphysema (CPFE) that is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis, and abnormalities of gas exchange. This syndrome frequently is complicated by pulmonary hypertension, acute lung injury, and lung cancer. The CPFE syndrome typically occurs in male smokers, and the mortality associated with this condition, especially if pulmonary hypertension is present, is significant. In this review, we explore the current state of the literature and discuss etiologic factors and clinical characteristics of the CPFE syndrome.

Compliance with CPAP Therapy in Older Men with Obstructive Sleep Apnea

OBJECTIVES: Factors specifically affecting compliance with continuous positive airway pressure (CPAP) in older patients with obstructive sleep apnea (OSA) have not been described. The purpose of this study is to determine which factors are associated with compliance and noncompliance in older patients, a growing segment of the population.

Inhibitors of oxidative ATP production cause transient vasoconstriction and block subsequent pressor responses in rat lungs.

We wondered if depression of oxidative adenosine triphosphate (ATP) production caused pulmonary vasoconstriction. If so, then several chemically different inhibitors of oxidative ATP production all should cause pulmonary pressor responses. The vascular reactivity of isolated, blood- perfused rat lungs was established by eliciting pressor responses to airway hypoxia and to intraarterial angiotensin II. Then, during normoxia, we added to perfusate one of five chemical inhibitors of oxidative ATP production: 10 μM azide, 1 μM cyanide, 1 μM dinitrophenol, 5 or 10 /IM antimycin A, or 0.5 JUM rotenone. Each of the five chemical inhibitors, but not their solvents, caused a transient pressor response, followed by loss of vascular reactivity to hypoxia, angiotensin II, and chemical inhibitors. The inhibitor pressor responses were not due to an effect on blood cells, since they also were seen in lungs perfused with plasma. The magnitudes of pressor responses to all metabolic inhibitors except azide correlated with the magnitudes of preceding pressor responses to hypoxia, but not to the preceding angiotensin II responses. When verapamil or calcium chloride was added to perfusate, the hypoxic and inhibitor pressor responses were blunted more than was the angiotensin II response. Thus, five chemically different substances, inhibiting different steps of oxidative ATP production, all caused pressor responses that were blocked readily by verapamil and by increased perfusate calcium chloride. These results support the possibility that depression of oxidative ATP production elicits pulmonary vasoconstriction that is dependent on influx of extracellular calcium. Hypoxia might also be sensed in the pulmonary circulation by decreased oxidative ATP production in some as yet unidentified lung cell. Circ Res 48: 393-400, 1981

Heterogeneity in Combined Pulmonary Fibrosis and Emphysema

Background: Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder described in several case series of upper lobe emphysema associated with lower lobe fibrosis. Patients with this entity have relatively preserved lung volumes and spirometry but marked reductions in diffusing capacity on pulmonary function testing. Smoking appears to be the predominant risk factor for this disorder. Usual interstitial pneumonia has been the most common histological pattern of interstitial lung disease described on biopsy in the literature. Objectives: To characterize the clinical, imaging and pathological features of a cohort of patients with CPFE. Methods: Retrospective review of electronic medical record data, radiological imaging, and available lung biopsy specimens for a series of 10 patients with CPFE at the Providence VA Medical Center, Providence, R.I., USA. Results: We describe a series of 10 patients with CPFE. All had severe reductions in diffusing capacity out of proportion to their lung volumes and spirometry. All had predominantly upper lobe emphysema on computed tomography; 8/10 had lower lobe subpleural reticular abnormalities and honeycombing, while 2 had lower lobe ground glass changes on imaging. These 2 patients demonstrated a pattern of interstitial lung disease on biopsy characterized by intra-alveolar macrophage accumulation in association with marked alveolar septal fibrosis, consistent with a variant form of desquamative interstitial pneumonia with extensive fibrosis. Conclusions: The imaging findings and pathology in patients with CPFE are heterogeneous.

Strategic Plan for Lung Vascular Research: An NHLBI-ORDR Workshop Report

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype-phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes.

Pulmonary arterial hypertension: new insights and new hope.

Abstract:  Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by abnormal increased vasoconstriction and vascular remodelling. In this review we discuss the pathophysiology, genetic basis and clinical features of this disorder. Current therapy of PAH is based on an understanding of its pathogenesis, and we review current treatment options based on the pathophysiology of the disease. We discuss three promising novel therapies studied in animal models and human tissue. All three therapies appear to prevent and reduce pulmonary arterial medial hyperplasia through their anti‐proliferative and/or pro‐apoptotic effects: serotonin transporter inhibitors by blocking serotonin uptake; dichloroacetate by activating voltage‐gated potassium channels; and simvastatin by preventing activation of small GTPases.

Leucocytoclastic vasculitis: an update for the clinician

Leucocytoclastic vasculitis is a small vessel inflammatory disease mediated mostly by deposition of immune complexes. Infections, medications, chemicals, bacteria, viruses, and diseases associated with immune complexes have been accused in the pathogenesis. Cutaneous leucocytoclastic vasculitis presents as palpable purpura most often localized in the lower extremities, often accompanied by abdominal pain, arthralgia and renal involvement. The clinical diagnosis of leucocytoclastic vasculitis is confirmed histopathologically by skin biopsy. In order to determine the cause of the disease, depending on the patients history, complete blood cell count, blood cultures, cryoglobulins, serum protein electrophoresis, rheumatoid factor, antinuclear antibody, and autoantibodies to neutrophilic cytoplasmic antigens and complement should be checked. Once the diagnosis of leucocytoclastic vasculitis is made, emphasis should be on the search for an etiological factor and the identification of the involved organs. If possible, the underlying cause should be treated or removed, for example discontinuation of drugs. The prognosis depends on the disease that has the cutaneous leucocytoclastic angiitis as a component, as well as the severity of internal organ involvement. For example, a patient with cutaneous leucocytoclastic angiitis and moderate nephritis as component of Henoch-Schonlein purpura has a much better prognosis than a patient with these same findings as a component of Wegeners granulomatosis. Only if physicians recognize and report severe reactions to regulatory authorities and manufacturers, new drugs associated with a risk of such reactions can be identified.Leucocytoclastic vasculitis is a small vessel inflammatory disease mediated mostly by deposition of immune complexes. Infections, medications, chemicals, bacteria, viruses, and diseases associated with immune complexes have been accused in the pathogenesis. Cutaneous leucocytoclastic vasculitis presents as palpable purpura most often localized in the lower extremities, often accompanied by abdominal pain, arthralgia and renal involvement. The clinical diagnosis of leucocytoclastic vasculitis is confirmed histopathologically by skin biopsy. In order to determine the cause of the disease, depending on the patients history, complete blood cell count, blood cultures, cryoglobulins, serum protein electrophoresis, rheumatoid factor, antinuclear antibody, and autoantibodies to neutrophilic cytoplasmic antigens and complement should be checked. Once the diagnosis of leucocytoclastic vasculitis is made, emphasis should be on the search for an etiological factor and the identification of the involved organs. If possible, the underlying cause should be treated or removed, for example discontinuation of drugs. The prognosis depends on the disease that has the cutaneous leucocytoclastic angiitis as a component, as well as the severity of internal organ involvement. For example, a patient with cutaneous leucocytoclastic angiitis and moderate nephritis as component of Henoch-Schonlein purpura has a much better prognosis than a patient with these same findings as a component of Wegeners granulomatosis. Only if physicians recognize and report severe reactions to regulatory authorities and manufacturers, new drugs associated with a risk of such reactions can be identified.

Focal adhesion kinase and endothelial cell apoptosis.

Focal adhesion kinase (FAK) is a key component of cell-substratum adhesions, known as focal adhesion complexes. Growing evidence indicates that FAK is important in maintenance of normal cell survival and that disruption of FAK signaling results in loss of substrate adhesion and anoikis (apoptosis) of anchorage-dependent cells, such as endothelial cells. Basal FAK activity in non-stimulated endothelial cells is important in maintaining cell adhesion to integrins via PI3 kinase/Akt signaling. FAK activity is dependent upon small GTPase signaling. FAK also appears to be important in cardiomyocyte hypertrophy and hypoxia/reoxygenation-induced cell death. This review summarizes the signaling pathways of FAK in prevention of apoptosis and the role of FAK in mediating adenosine and homocysteine-induced endothelial cell apoptosis and in cardiovascular diseases.

An Official American Thoracic Society Statement: Pulmonary Hypertension Phenotypes

BACKGROUND Current classification of pulmonary hypertension (PH) is based on a relatively simple combination of patient characteristics and hemodynamics. This limits customization of treatment, and lacks the clarity of a more granular identification based on individual patient phenotypes. Rapid advances in mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define PH phenotypes on the basis of biomarkers, advanced imaging, and pathobiology. This document organizes our current understanding of PH phenotypes and identifies gaps in our knowledge. METHODS A multidisciplinary committee with expertise in clinical care (pulmonary, cardiology, pediatrics, and pathology), clinical research, and/or basic science in the areas of PH identified important questions and reviewed and synthesized the literature. RESULTS This document describes selected PH phenotypes and serves as an initial platform to define additional relevant phenotypes as new knowledge is generated. The biggest gaps in our knowledge stem from the fact that our present understanding of PH phenotypes has not come from any particularly organized effort to identify such phenotypes, but rather from reinterpreting studies and reports that were designed and performed for other purposes. CONCLUSIONS Accurate phenotyping of PH can be used in research studies to increase the homogeneity of study cohorts. Once the ability of the phenotypes to predict outcomes has been validated, phenotyping may also be useful for determining prognosis and guiding treatment. This important next step in PH patient care can optimally be addressed through a consortium of study sites with well-defined goals, tasks, and structure. Planning and support for this could include the National Institutes of Health and the U.S. Food and Drug Administration, with industry and foundation partnerships.