Lung Function and Airway Hyperresponsiveness in Adult Patients with Sickle Cell Disease

Vendramini, Elisa Cristina; Vianna, Elcio Oliveira; Ðngulo, Ivan De Lucena; Castro, Flavia Bueno De; Martínez, José Antônio Baddini; Terra-Filho, João

doi:10.1097/00000441-200608000-00003

Cited by 37 publications

(32 citation statements)

References 21 publications

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“…Restrictive lung disease develops with increasing age. 11,[35][36][37] In addition, increased incidence of PHT develops with increasing age. 9,12,13 NO and ET-1 are opposing forces that determine the pulmonary vascular tone.…”

Section: Discussionmentioning

confidence: 99%

Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1α

Patel

Gonsalves

Malik

et al. 2008

Blood

111

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Pulmonary hypertension (PHT) develops in sickle cell disease (SCD) and is associated with high mortality. We previously showed that erythroid cells produce placenta growth factor (PlGF), which activates monocytes to induce proinflammatory cytochemokines, contributing to the baseline inflammation and severity in SCD. In this study, we observed that PlGF increased expression of endothelin-1 (ET-1) and endothelin-B receptor (ET-BR) from human pulmonary microvascular endothelial cells (HPMVECs) and monocytes, respectively. PlGF-mediated ET-1 and ET-BR expression occurred via activation of PI-3 kinase, reactive oxygen species and hypoxia inducible factor-1␣ (HIF-1␣). PlGF increased binding of HIF-1␣ to the ET-1 and ET-BR promoters; this effect was abrogated with mutation of hypoxia response elements in the promoter regions and HIF-1␣ siRNA and confirmed by chromatin immunoprecipitation analysis. Furthermore, PlGF-mediated ET-1 release from HPMVECs and ET-BR expression in monocytes creates a PlGF-ET-1-ET-BR loop, leading to increased expression of MCP-1 and IL-8. Our studies show that PlGF-induced expression of the potent vasoconstrictor ET-1 and its cognate ET-BR receptor occur via activation of HIF-1␣, independent of hypoxia. PlGF levels are intrinsically elevated from the increased red cell turnover in SCD and in other chronic anemia (eg, thalassemia) and may contribute to inflammation and PHT seen in these diseases. (Blood. 2008;112:856-865) IntroductionThe clinical manifestations of sickle cell disease (SCD) include chronic hemolytic anemia, frequent infections, and intermittent episodes of vascular occlusion. [1][2][3][4][5][6] Pulmonary disease, both acute and chronic, is the second most common cause of hospitalization and a leading cause of both morbidity and mortality in adults with SCD. 1,[7][8][9] The most frequent form of acute pulmonary disease is the acute chest syndrome (ACS), which occurs in 15% to 40% of patients with SCD. 10 Pulmonary hypertension (PHT) occurs in both adults and children with SCD: it develops with increasing age and portends an extremely poor prognosis. PHT is a significant risk factor for early mortality in SCD. 9,[11][12][13] Studies have shown that there is a clinical syndrome of hemolysis-associated PHT in SCD 9 that results from global impairment in nitric oxide (NO) bioavailability from its quenching by free heme. 14 It is known that vascular tone is also modulated by vasoconstrictors such as endothelin-1 (ET-1). Studies have shown increased plasma levels of ET-1 in patients with SCD and ACS. 15,16 Tissue hypoxemia due to microvascular occlusion and chronic mild-moderate desaturations in SCD may contribute to increased levels of ET-1, which is released from endothelial cells in response to hypoxia. 17 Increased levels of ET-1, if sustained as a result of the underlying SCD pathophysiology, can contribute to the development of PHT.SCD is also characterized by presence of a chronic inflammatory state manifested by leukocytosis and monocytosis and increased circulating levels of p...

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Section: Discussionmentioning

confidence: 99%

Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1α

Patel

Gonsalves

Malik

et al. 2008

Blood

111

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“…Vendramini and colleagues investigated the prevalence of airway hyper-responsiveness in adult sickle cell patients, as it has been noted in children (159). Their study suggests that there is a high prevalence of airway hyperresponsiveness in adult patients with SCD without a history of reactive airway disease.…”

Section: Sickle Cell Diseasementioning

confidence: 97%

NOX Modifiers—Just a Step Away from Application in the Therapy of Airway Inflammation?

Wieczfińska

Sokołowska

Pawliczak

2015

Antioxidants & Redox Signaling

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Significance: NADPH oxidase (NOX) enzymes, which are widely expressed in different airway cell types, not only contribute to the maintenance of physiological processes in the airways but also participate in the pathogenesis of many acute and chronic diseases. Therefore, the understanding of NOX isoform regulation, expression, and the manner of their potent inhibition might lead to effective therapeutic approaches. Recent Advances: The study of the role of NADPH oxidases family in airway physiology and pathophysiology should be considered as a work in progress. While key questions still remain unresolved, there is significant progress in terms of our understanding of NOX importance in airway diseases as well as a more efficient way of using NOX modifiers in human settings. Critical Issues: Agents that modify the activity of NADPH enzyme components would be considered useful tools in the treatment of various airway diseases. Nevertheless, profound knowledge of airway pathology, as well as the mechanisms of NOX regulation is needed to develop potent but safe NOX modifiers. Future Directions: Many compounds seem to be promising candidates for development into useful therapeutic agents, but their clinical potential is yet to be demonstrated. Further analysis of basic mechanisms in human settings, high-throughput compound scanning, clinical trials with new and existing molecules, and the development of new drug delivery approaches are the main directions of future studies on NOX modifiers. In this article, we discuss the current knowledge with regard to NOX isoform expression and regulation in airway inflammatory diseases as well as the aptitudes and therapeutic potential of NOX modifiers. Antioxid. Redox Signal. 23,[428][429][430][431][432][433][434][435][436][437][438][439][440][441][442][443][444][445]

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“…Airway hyper-responsiveness and pulmonary function abnormalities are more common in children and adults with SCD than in the general population, suggesting that these clinical features of asthma may be related to the pathogenesis of SCD [52][53][54][55][56][57][58] (Table 1). Measures of airway hyperresponsiveness are thought to be relatively specific for the diagnosis of asthma in children and adults in the general population.…”

Section: Evidence To Suggest That Asthma Symptoms Are a Manifestationmentioning

confidence: 99%

Asthma and sickle cell disease: two distinct diseases or part of the same process?

Field¹,

DeBaun²

2009

Hematology

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A physician diagnosis of asthma in children and adults with sickle cell disease (SCD) has been associated with increased rates of pain and acute chest syndrome (ACS) episodes and premature death. Despite the clinical significance of a doctor’s diagnosis of asthma in individuals with SCD, the criteria for a physician diagnosis of asthma are not well defined. Many features of asthma are common in individuals with SCD, including symptoms of wheezing, obstructive lung disease and airway hyper-responsiveness. However, it is not clear if these signs and symptoms of asthma reflect a physician diagnosis of asthma, or if these asthma features are related to SCD. Further complicating the diagnosis of asthma in children with SCD is the significant overlap in clinical manifestations between an asthma exacerbation and an ACS episode. Evidence supporting the concept that asthma and SCD are separate co-morbid conditions includes a similar prevalence of asthma between children with SCD and those in the general population and the observation that asthma is inherited in a familial pattern in the families of children with SCD. In contrast, there is significant evidence that asthma-like features may be associated with SCD without a diagnosis of asthma, including a higher than expected prevalence of airway hyper-responsiveness and obstructive lung disease. Regardless of whether SCD and asthma are distinct or overlapping co-morbid conditions, we recommend a systematic and complete evaluation of asthma when the diagnosis is suspected or when patients have multiple episodes of pain or ACS.

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Lung Function and Airway Hyperresponsiveness in Adult Patients with Sickle Cell Disease

Cited by 37 publications

References 21 publications

Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1α

Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1α

NOX Modifiers—Just a Step Away from Application in the Therapy of Airway Inflammation?

Asthma and sickle cell disease: two distinct diseases or part of the same process?

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