Anakinra (IL‐1R antagonist) lowers pulmonary artery pressure in a neonatal surfactant depleted piglet model

Chada, Martin; Nögel, S; Schmidt, A.; Rückel, Aline; Bosselmann, S; Walther, Julia; Papadopoulos, Thomas; Hardt, Katharina von der; Dötsch, Jörg; Rascher, Wolfgang; Kandler, Michael Andreas

doi:10.1002/ppul.20851

Cited by 13 publications

(14 citation statements)

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“…Therefore, the mechanisms responsible for the decrease in macrophage infiltration by A-740003 may be caused by a specific decrease in IL-1β. Both caspase-1 and IL-1β have been shown to participate in the pathogenesis of experimental PH in gene knockout and specific antagonist studies [8, 48, 49]. Therefore, P2X 7 R potentially has roles in PH by mediating NLRP3 inflammasome activation and IL-1β secretion.…”

Section: Discussionmentioning

confidence: 99%

Role of P2X7R in the development and progression of pulmonary hypertension

et al. 2017

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BackgroundPulmonary arterial hypertension (PAH) is a devastating disease that lacks sufficient treatment. Studies have shown that the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome contributes to PAH pathogenesis, but the role of the upstream molecular P2X7 receptor (P2X7R) has remained unexplored. We investigated the role of P2X7R in the pathogenesis of PAH.Methods and resultsPH was induced by a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) on left pneumonectomised Sprague-Dawley rats, as validated by significant increases in pulmonary artery pressure and vessel wall thickness. Marked P2X7R was detected by predominant PA immunostaining in lungs from PH rats. Western blot revealed a significant increase in the protein levels of P2X7R as well as NLRP3 and caspase-1 in the diseased lung tissue compared with normal tissue. The rats received A-740003 (a selective P2X7 receptor antagonist, 30 mg/kg) daily starting from 1 week before or 2 weeks after MCT injection. Consequently, A-740003 reversed the NLRP3 inflammasome upregulation, significantly decreased the mean right ventricular (RV) pressure and RV hypertrophy, and reversed pulmonary arterial remodelling 4 weeks after MCT injection, as both a pretreatment and rescue intervention. Notably, A-740003 significantly reduced macrophage and pro-inflammatory cytokine levels, as measured via bronchoalveolar lavage. The recruitment of macrophages as well as collagen fibre deposition in the perivascular areas were also reduced, as confirmed by histological staining.ConclusionsP2X7R contributes to the pathogenesis of PH, probably in association with activation of the NLRP3 inflammasome. Blockade of P2X7R might be applied as a novel therapeutic approach for the treatment of PAH.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0603-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Role of P2X7R in the development and progression of pulmonary hypertension

et al. 2017

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“…Increased BAL IL-1Ra has been shown in patients with ARDS, and is proposed as a potential endogenous antiinflammatory mediator to limit damage in acute lung injury (ALI) (37). Mesenchymal stem cells, which reduce lung injury in animal models, are associated with increased pulmonary IL-1Ra concentrations (38), whereas aerosolized Anankinra, recombinant human IL-1Ra, reduced pulmonary arterial pressure and gene expression of IL-8 and IL-1b in a porcine model of lung injury, suggesting a reparative role for exogenous IL-1Ra (39). Finally, exogenous IL-1Ra reduced pulmonary edema and protein permeability in a rodent model of ventilator-induced lung injury (40).…”

Section: Discussionmentioning

confidence: 99%

Keratinocyte Growth Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

Shyamsundar

McAuley

Ingram

et al. 2014

Am J Respir Crit Care Med

104

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Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS.Methods: Volunteers were randomized to intravenous KGF (60 mg/kg) or placebo for 3 days, before inhaling 50 mg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein.In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.Conclusions: KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895.

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“…In addition, IL1RA has shown therapeutic promise in animal models of ARDS (61,62), and is a critical mediator of the beneficial effect of mesenchymal stem cells in models of lung injury (63). There is strong evidence that an individual's response to infection and injury has a heritable component (64,65), and IL1RN is one of many cytokine genes exhibiting significant variation between ancestries (66,67).…”

Section: Discussionmentioning

confidence: 99%

IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

Meyer

Feng

et al. 2013

Am J Respir Crit Care Med

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Rationale: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete. Objectives: To identify genetic risk variants for ARDS using large scale genotyping. Methods: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n ¼ 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P , 5 3 10 24 for replication in stage II, a trauma case-control population (n ¼ 778). SNPs replicating their association in stage II (P , 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n ¼ 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDSassociated genotype and plasma protein levels. Measurements and Main Results: A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P , 0.004) and III (P , 0.02), and was robust to clinical adjustment (combined odds ratio ¼ 0.81; P ¼ 4.2 3 10 25 ). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN. Conclusions: The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.Keywords: functional genetic polymorphism; acute lung injury; acute respiratory distress syndrome; IL-1 receptor antagonist; replication Acute respiratory distress syndrome (ARDS) is a syndrome characterized by acute bilateral alveolar flooding and severe hypoxemia in the absence of clinical heart failure (1, 2). ARDS afflicts an estimated 190,000 people annually in the United States, and carries a mortality of between 30 and 40% (3). The syndrome can emerge after a variety of potential inciting events, such as sepsis, pneumonia, aspiration, and trauma. However, the risk of ARDS after potential at-risk injuries is not uniform; it appears that individual genetic variation contributes to a patient's susceptibility to ARDS (4, 5). The pathophysiology underlying ARDS remains imprecisely understood, but dysregulated inflammation and altered permeability of the alveolocapillary membrane seem Supported by National Institutes of Health (NIH) grants to fund the study populations, Hospital of the University of Pennsylvania (HL060290, HL079063), Harborview (GM066946), and Massachusetts General Hospital (HL060710). Additional NIH grants RC2HL101770, HL081619, HL090021, and HL102254 supported the genetic and molecular investigations described herein. The genetic determinants of acute respiratory distress syndrome (ARDS) susceptibility remain incompletely u...

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Anakinra (IL‐1R antagonist) lowers pulmonary artery pressure in a neonatal surfactant depleted piglet model

Cited by 13 publications

References 25 publications

Role of P2X7R in the development and progression of pulmonary hypertension

Role of P2X7R in the development and progression of pulmonary hypertension

Keratinocyte Growth Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

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