Lipid Mediator Dysregulation in Primary Pulmonary Hypertension

doi:10.1378/chest.114.3_Supplement.205S

Chest

Volume 114, Issue 3, Supplement, September 1998, Pages 205S-207S

https://doi.org/10.1378/chest.114.3_Supplement.205S Get rights and content

The characteristic arteriopathy of primary pulmonary hypertension (PPH) with attendant endothelial dysfunction provides an opportunity for enhanced cellular activation in the lung. Data from many laboratories support the concept of altered eicosanoid metabolism in PPH. Rigorously quantitative measurements of the excretion of metabolites of thromboxane A₂ and prostacyclin support persistent platelet activation and inadequate endothelial response in patients with PPH. Recent studies measuring excretion of prostaglandin D₂ metabolites suggest that additional cell sources, such as activated tissue macrophages, may also play a role in the observed elevation in thromboxane excretion and possibly in the pathogenesis of the vascular remodeling. Additional research examining in vivo cell activation in patients receiving therapy with long-term infusion of prostacyclin may further our understanding of the pathogenesis of PPH.

Section snippets

Vasoactive Eicosanoids of the Vessel Wall

A panoply of mediators regulates interactions between circulating platelets and leukocytes and the vascular endothelium. Pivotal roles have been described for metabolites of arachidonic acid, including prostacyclin (PGI₂) and thromboxane A₂ (TxA₂).² Formation of cyclic endoperoxide precursors (PGG₂ and PGH₂) and metabolic conversion to specific bioactive eicosanoids depends on several factors: (1) liberation of arachidonic acid from membrane phospholipids by the actions of cellular

Evidence for Dysregulation of Eicosanoid Function in PPH

Data from many laboratories now provides evidence of endothelial dysfunction and disturbed eicosanoid synthesis in patients with PPH. In 1987, Rich and colleagues,¹² in a study of thromboxane synthase inhibition in 10 patients with PPH, provided data suggestive of altered lipid metabolism that documented decreased levels of serum 6-keto-PGF₁. Two years later, Badesch and coworkers¹³ examined eicosanoid synthesis in an experimental model of pulmonary hypertension—neonatal calves exposed to

Future Directions

Much information about the role of eicosanoid mediators in pulmonary hypertension is still lacking. With the advent of effective therapy with continuous infusion of PGI₂ (Flolan; Glaxo-Wellcome), this relative autocoid deficiency can be abolished with therapeutic benefit.¹⁶ However, the mechanism(s) of the beneficial effect of this therapy remain unclear. Is there effective in vivo suppression of platelet and macrophage activation? Does this therapy induce regression of the pulmonary

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Besides its potent vasodilatory effect, prostacyclin has pronounced aggregation-inhibiting [52–54], anti-inflammatory [55] and anti-proliferative [56, 57] properties. The use of prostacyclin in the therapy of pulmonary hypertension has been supported by studies demonstrating reduced release of endogenous prostacyclin in patients with primary pulmonary hypertension [15, 58] secondary to downregulation of prostacyclin synthase [59]. First evidence of favorable hemodynamic effects of infused prostacyclin in the pulmonary circulation assessed by right-heart catheterization was reported in 1980 [60].
Pulmonary arterial hypertension (PAH) is a rare, but severe and life-threatening disease characterized by vasoconstriction and remodeling of the pulmonary arterioles, leading to progressive increase in pulmonary vascular resistance and ultimately to right-heart failure. In the last two decades, significant progress in treatment of PAH has been made, with currently 12 drugs approved for targeted therapy. Among these, the stable prostacyclin analogues iloprost and treprostinil have been repurposed for inhalation. The paper highlights the development of the two drugs emphasizing the rationale and advantages of the inhalative approach.
Despite substantial advances in the specific, mainly vasodilatory PAH therapy, disease progression is mostly inevitable and mortality remains unacceptably high. Thus, introduction of new drugs targeting the cancer-like remodeling of the diseased pulmonary arteries is urgently needed. Inhalation offers pulmonary selectivity and will hopefully pioneer the repurposing of novel highly potent drugs for effective aerosol therapy of PAH.
Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability
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Thus, increased levels of HNE not only confirm presence of OS in PAH patients but also contribute to the pathologic remodeling of the pulmonary vasculature typical of the disease. Early on, the role of FA and lipid metabolites in the development of PAH have mainly addressed changes in the eicosanoid profile [2,61,69,70] and subsequently provided rationale for targeting the prostacyclin (PGI2) pathway [12]. Nowadays there is accumulating evidence on the role of FAs and their metabolism on the arginine–NOS–NO signaling [43,56,79].
Pulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed.
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Bioactive derivatives of polyunsaturated fatty acids (most importantly, arachidonic acid, EPA, and DHA) regulate essential aspects of lung function. These mediators include prostaglandins, isoprostanes, leukotrienes, lipoxins, and resolvins. They exert synergistic and opposing effects on bronchial constriction and relaxation, pulmonary vascular tone, and/or the initiation and cessation of immune and inflammatory responses in the lung. The identification in lung tissues of specific receptors for these mediators, as well as the lipid-responsive PPAR-α and PPAR-γ transcription factors, suggests that they are important in maintaining lung homeostasis. Several fatty acid-derived mediators (or their synthetic agonists or antagonists) have demonstrated therapeutic value in correcting derangements of lung function in asthma, pulmonary hypertension, inflammatory lung disease, fibrosis, or acute lung injury.
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Pulmonary hypertension (PH) is a known complication of Gaucher disease (GD) and splenectomy. Although it resembles World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH), PH due to GD or splenectomy is part of WHO group 5. There are no clinical trials testing therapies in PH due to GD or splenectomy. Several reports suggest that PAH-specific therapies are beneficial in patients with PH due to GD, although data are insufficient to formulate a treatment algorithm for these patients. The tyrosine kinase inhibitor imatinib has been investigated in the treatment of severe PAH, but not in PH WHO group 5. We report a patient with GD and splenectomy who developed PH that progressed while on conventional PAH-specific therapy and improved once imatinib was added to her treatment regimen. This is the first report, to our knowledge, describing significant subjective and objective improvements in response to imatinib in a patient with WHO group 5 PH.
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Citation Excerpt :
An important mediator in endothelial homeostasis, prostacyclins cause vasodilatation, inhibit platelet aggregation, and have anti-proliferative properties. The early finding that PAH patients are deficient in prostacyclin led to a natural interest in the use of prostacyclin replacement for therapeutic purposes.7,8 In the 1990s, case series and a small trial of IPAH patients treated with continuous epoprostenol, a synthetic prostacyclin derivative, showed significant improvements in pulmonary hemodynamics, functional capacity, and subjective symptoms, leading to the landmark multi-center randomized trial published in 1996 (Fig. 1 and Table 1).9-11
Major advances have been made in the treatment of World Health Organization Group 1 pulmonary arterial hypertension (PAH). Since the mid-1990s, nine medications have become available in the United States to target three key pathophysiologic derangements in PAH – the prostacyclin, endothelin, and nitric oxide pathways. As a group, these agents have led to improvements in functional capacity, symptoms, hemodynamics, and survival. Most patients with mild to moderate PAH are started on orally active agents such as endothelin receptor antagonists or phosphodiesterase inhibitors. Patients with more severe disease, particularly those with evidence of right heart failure, should be treated with continuous prostacyclin infusion or a combination of a prostacyclin and oral therapy. Each medication has unique properties and clinical considerations, and the selection of an appropriate therapy must be tailored to the individual patient. None of the currently available WHO Group 1 PAH therapies are curative, however, and it is the hope that new therapies in development may halt or reverse disease progression. This review will discuss the major therapeutic classes of presently available medications and their role in managing the patient with PAH. We will also review data supporting the use of combination therapy, adjuvant background therapy, and new agents currently under investigation.
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: Supported by PPH Cure Foundation, NIH NHLBI HL-55198, HL-19153, and HL-55649

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Chest

Brenot Memorial Symposium on the Pathogenesis of Primary Pulmonary HypertensionLipid Mediator Dysregulation in Primary Pulmonary Hypertension

Section snippets

Vasoactive Eicosanoids of the Vessel Wall

Evidence for Dysregulation of Eicosanoid Function in PPH

Future Directions

J Biol Chem

Blood

Chest

Heterogeneity of pathologic lesions in familial primary pulmonary hypertension

Am Rev Respir Dis

Enhanced prostacyclin and thromboxane A2 synthesis in vivo in ischemic heart disease: non-invasive evidence of sporadic platelet activation in unstable angina

Circulation

Prostaglandin biosynthesis and it compartmentalization in vascular smooth muscle and endothelial cells

Ann Rev Physiol

Lipid mediator synthesis by lung macrophages

Brenot Memorial Symposium on the Pathogenesis of Primary Pulmonary Hypertension
Lipid Mediator Dysregulation in Primary Pulmonary Hypertension

Enhanced prostacyclin and thromboxane A₂ synthesis in vivo in ischemic heart disease: non-invasive evidence of sporadic platelet activation in unstable angina