Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension

Cracowski, Jean‐Luc; Chabot, F.; Labarère, José; Faure, Patrice; Degano, Bruno; Schwebel, Carole; Chaouat, Ari; Reynaud‐Gaubert, Martine; Cracowski, Claire; Sitbon, Olivier; Yaïci, Azzedine; Simonneau, Gérald; Humbert, Marc

doi:10.1183/09031936.00151313

Cited by 111 publications

(102 citation statements)

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“…Like the study by CRACOWSKI et al [21], the patient sample size is relatively modest (76 patients), although in this case the sex ratio (female/male 81%) is more consistent with that expected for PAH. Unlike the study by CRACOWSKI et al [21], in which there is almost strict homogeneity, this is more of a mixed population from group 1 disease in the Cleveland study, and a vast majority of patients are already on therapy at the time of blood drawing. Using ROC curve analysis, the investigators demonstrate that IL-6 had better discrimant ability to predict mortality compared to CRP.…”

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confidence: 81%

“…The first letter by CRACOWSKI et al [21] from the French Network of Pulmonary Hypertension used a multicentre prospective cohort study of idiopathic, heritable and drug or toxin-induced PAH patients followed during a period of 3 years and for whom a biobank of plasma was stored. Using a multivariable Cox proportional hazards model, the authors demonstrated that increased levels of various cytokines (such as IL-1a, IL-1b, TNF-a and IL-13, measured by a highly sensitive multiplex assay) independently predicted higher mortality.…”

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confidence: 99%

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Inflammation in pulmonary arterial hypertension: is it time to quell the fire?

Hassoun

2014

European Respiratory Journal

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@ERSpublications Two new studies demonstrate an association between circulating inflammatory mediators and mortality in PAH http://ow.ly/szrQo Inflammare, or to set ablaze, is the Latin origin of the word inflammation, a physical condition that was undoubtedly already familiar to the ancient Egyptians and Greeks. It is, however, the Roman Aulus Celsus who is credited with describing, in the first century AD, the four cardinal signs of inflammation consisting of rubor et tumor cum calore et dolore (redness and swelling with heat and pain). Two centuries later, Galen promoted the humoral view of inflammation as a potential part of the healing process rather than a pure pathological process, and may have proposed the fifth cardinal sign (functio laesa or loss of function) [1], although this is also attributed to Virchow in the 19th century [2]. And while we now know that, in many pathologies characterised by inflammation, the initial four cardinal signs can be subclinical and silent, it is clear that for Virchow inflammation was ultimately pathologic since it lead to loss of function.What is then going on in pulmonary arterial hypertension (PAH)? Over the past 120 years since the first pathologic description of ''pulmonary vascular sclerosis'' by Romberg, our understanding of the remodelling process underlying what we now call PAH has greatly changed from a mere description of the thickening of the three components of the pulmonary vascular wall leading to narrowing of the lumen, to aberrant cellular proliferation (e.g. endothelial and smooth muscle cells and fibroblasts) and influx of inflammatory cells in and around the various components of the vascular wall. TUDER et al. [3] were among the first to describe a significant influx of inflammatory cells, including macrophages and lymphocytes, into the plexiform lesions of hypertensive pulmonary vessels. Within a few years, other markers of inflammation, including macrophage inflammatory protein-1a, interleukin (IL)-1b and 5], and P-selectin [6], as well as mediators of the lipoxygenase pathway (e.g. 5-lipoxygenase and 5-lipoxygenase activating protein or FLAP) [7,8] were found to be highly expressed in severe idiopathic PAH in human disease, as well as in animal models. The association between inflammation and vascular remodelling was further strengthened by the observation of circulating antibodies [9] (e.g. antibodies to endothelial cells [10,11] and fibroblasts [12]) in PAH and association of this syndrome with certain autoimmune (e.g. connective tissue diseases [13] and thyroiditis) and infectious (e.g. HIV) [14] diseases. In fact there has been over the past few decades an exponential rise of articles in the literature dealing with the role of inflammation in PAH [15]. As PAH specialised centres have started collecting sera from patients in a prospective fashion, an explosion of inflammatory markers have been identified in association with PAH, including cytokines [16,17], cytokinelike hormones [18], and angiogenic modulatory proteins with potential inflammato...

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confidence: 81%

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confidence: 99%

Inflammation in pulmonary arterial hypertension: is it time to quell the fire?

Hassoun

2014

European Respiratory Journal

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“…Increasing evidence has suggested that high levels of IL-1β predict a worse outcome in patients with severe PAH [5,6,15]. However, despite its prognostic value, no prospective study has explored whether treatment with PAH-specific pharmacotherapies lowers IL-1β or whether lowering cytokine levels can affect survival.…”

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confidence: 99%

Pulmonary arterial hypertension and the Enigma code of smouldering inflammation

2016

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@ERSpublications Anti-interleukin-1 treatment for pulmonary arterial hypertension: are we there yet? http://ow.ly/8irv300EXooMore than any other cytokine family, the [interleukin]-1 family is closely linked to innate inflammatory and immune responses. DINARELLO [1]"What causes fever?" was the question that prompted the work that led to the discovery of the "leukocyte pyrogen", eventually named interleukin (IL)-1, in the late 1970s [1]. However, despite the rapid understanding of innate and adaptive immune responses and inflammation during the 1980s, it was not until 1995 that HUMBERT et al. [2] reported that both IL-1 and IL-6 levels were increased in the plasma of patients with idiopathic pulmonary arterial hypertension (PAH), thus revealing an inflammatory component in the pathogenesis of severe PAH. Ever since the first report by HUMBERT et al.[2], the role of inflammation as a cause or consequence of PAH has remained controversial [3] and this ongoing debate has perhaps prevented the pragmatism to design clinical trials to test novel anti-inflammatory therapies in patients with PAH.In the current issue of the European Respiratory Journal, PARPALEIX et al. [4] provide one more mechanistic piece of evidence to solve the enigma of aseptic inflammation in PAH and offer another rationale to justify the clinical evaluation of IL-1-based treatment strategies for PAH. The authors demonstrated that the levels of the IL-1 receptor 1 (IL1R1) protein and its adaptor protein MyD88, required for downstream signalling, are increased in the lung tissue samples from patients with idiopathic PAH. They also showed that in mice with chronic hypoxia-induced PAH and in rats with monocrotaline-induced PAH, treatment with anakinra, a recombinant IL1R1 antagonist, decreased pulmonary vascular muscularisation, right ventricular systolic pressure and right ventricular hypertrophy. The study by PARPALEIX et al. [4] confirmed earlier studies that had demonstrated the increased expression of IL-1α and IL-1β protein levels in monocrotaline-induced pulmonary hypertensive rat lungs and that chronic treatment with anakinra prevented the development of monocrotaline-induced PAH [5]. To further assess causality, PARPALEIX et al.[4] challenged both IL1R1 and MyD88 knock-out mice with chronic hypoxia, and showed that genetic ablation of the IL-1β canonical signalling machinery ameliorated the pulmonary vascular response to hypoxia. In vitro, they showed how pulmonary vascular smooth muscle cells treated with anakinra had reduced IL-1β-induced cell proliferation, NF-κB activation (a major inflammatory regulator) and IL-6 expression (an IL-1β-inducible cytokine linked to increased mortality in PAH [6,7]). Moreover, supernatants from M1-polarised macrophages resulted in pulmonary vascular smooth muscle cell proliferation, partly via IL1R1/MyD88 signalling. However, some questions remain unanswered. For example, 1) what is the mechanism whereby

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“…Similarly, various markers of inflammation such as cytokines and chemokines are expressed in human disease, as well as in animal models of PH, in the lung tissue or in the circulation [16][17][18][19][20][21], and circulating antibodies have been detected [11,[22][23][24]. Many of these inflammatory biomarkers can predict survival [13,25,26].…”

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confidence: 99%

“…Inflammation has been increasingly recognised in the pathogenesis of pulmonary arterial hypertension (PAH) (group 1 of the PH classification), as suggested by the continuous flurry of studies and articles devoted to the subject [9][10][11][12][13][14]. In addition to the aberrant cellular proliferation (e.g.…”

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confidence: 99%

Inflammation in chronic thromboembolic pulmonary hypertension: accomplice or bystander in altered angiogenesis?

Hassoun

2015

Eur Respir J

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@ERSpublicationsEvidence for the role of inflammation in the pathogenesis of PAH: a new study demonstrates inflammation in CTEPH http://ow.ly/OxixF Chronic thromboembolic pulmonary hypertension (CTEPH) is not an uncommon cause of pre-capillary pulmonary hypertension (PH). It is thought to be a long-term complication of symptomatic or asymptomatic pulmonary embolism (PE) or venous thromboembolism (VTE) [1][2][3]. It now appears clear from a retrospective analysis of large European registries [4] and an international prospective registry [5] that CTEPH, as its name indicates, is somehow associated with one or multiple thromboembolic events. However, the reason why a minority of patients (∼0.1-9%) [6,7] who suffer an initial VTE or PE eventually develop CTEPH while the vast majority manage to resolve their clot and resume normal life remains an enigma. Some clues into the aetiology of the disease are provided by the identification of predisposing factors found in epidemiological studies [4], such as infection (osteomyelitis) and malignancy, indwelling catheters or ventriculo-atrial shunts, splenectomy, chronic inflammatory conditions (e.g. inflammatory bowel disease), and genetic predisposition involving the coagulation system [4,6].

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Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension

Cited by 111 publications

References 12 publications

Inflammation in pulmonary arterial hypertension: is it time to quell the fire?

Inflammation in pulmonary arterial hypertension: is it time to quell the fire?

Pulmonary arterial hypertension and the Enigma code of smouldering inflammation

Inflammation in chronic thromboembolic pulmonary hypertension: accomplice or bystander in altered angiogenesis?

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