Systemic calcitonin gene-related peptide receptor antagonism decreases survival in a porcine model of polymicrobial sepsis: blinded randomised controlled trial

Messerer, David Alexander Christian; Datzmann, Thomas; Baranowsky, Anke; Peschel, Leandra; Hoffmann, Andrea; Gröger, Michael; Amling, Michael; Wepler, Martin; Nußbaum, Benedikt; Jiang, Shan; Knapstein, P.; Donat, Antonia; Calzia, Enrico; Radermacher, Peter; Keller, Johannes

doi:10.1016/j.bja.2021.11.042

Cited by 11 publications

(13 citation statements)

References 35 publications

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“…We can only speculate regarding this different result, but the reduced activity of the von Willebrand Factor (vWF) in our Bretoncelles-Meishan-Willebrand pigs may assume importance in this context. We studied heterozygous individuals of this swine strain, because they closely mimic the human coagulation system ( 24 , 25 , 32 , 33 ), in contrast to the hypercoagulatory state in other domestic swine strains ( 34 ). We cannot exclude, however, that this “vWF-disease”, albeit not presenting with any clinically relevant bleeding disorder, may have altered the STS effect on the GR expression: ACTH secreting bronchial carcinoid cells were shown to present with significant glucocorticoid receptor expression ( 38 ), and high glucocorticoid levels due to Cushing’s disease are associated with increased vWF-activity ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

“…Pigs were of the Bretoncelles-Meishan-Willebrand strain. This strain has reduced activity of the von Willebrand Factor (vWF), thereby mimicking the human coagulation system ( 24 , 25 , 32 , 33 ), in contrast to the hypercoagulatory state in domestic swine strains ( 34 ). Animals were sheltered at Oberberghof, Ulm, Germany, until further use with an acclimatization period of at least two weeks.…”

Section: Methodsmentioning

confidence: 99%

“…The experimental procedure and treatment regimen is summarized in Figure 1A and closely mimics previously described experiments ( 22 , 24 , 32 , 35 ). Prior to the initiation of hemorrhagic shock after the instrumentation (1-2 h) and a resting period (total of 4 h), baseline data was collected (−0.5 h in Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…Hemodynamics, gas exchange (calorimetric O 2 uptake and CO 2 production), arterial blood gas tensions, acid-base status, glucose, lactate, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), aspartate transaminase (AST), alanine transaminase (ALT), 8-Isoprostane, bilirubin, and troponin were determined as described previously ( 32 , 35 – 37 ). In brief, blood gas analysis, glucose, and lactate levels were measured using a standard blood gas analyzer (ABL 800 Flex, Radiometer GmbH, Krefeld, Germany).…”

Section: Methodsmentioning

confidence: 99%

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The H2S Donor Sodium Thiosulfate (Na2S2O3) Does Not Improve Inflammation and Organ Damage After Hemorrhagic Shock in Cardiovascular Healthy Swine

Messerer

Gaessler²,

Hoffmann

et al. 2022

Front. Immunol.

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We previously demonstrated marked lung-protective properties of the H2S donor sodium thiosulfate (Na2S2O3, STS) in a blinded, randomized, controlled, long-term, resuscitated porcine model of swine with coronary artery disease, i.e., with decreased expression of the H2S-producing enzyme cystathionine-γ-lyase (CSE). We confirmed these beneficial effects of STS by attenuation of lung, liver and kidney injury in mice with genetic CSE deletion (CSE-ko) undergoing trauma-and-hemorrhage and subsequent intensive care-based resuscitation. However, we had previously also shown that any possible efficacy of a therapeutic intervention in shock states depends both on the severity of shock as well as on the presence or absence of chronic underlying co-morbidity. Therefore, this prospective, randomized, controlled, blinded experimental study investigated the effects of the STS in cardiovascular healthy swine. After anesthesia and surgical instrumentation, 17 adult Bretoncelles-Meishan-Willebrand pigs were subjected to 3 hours of hemorrhage by removal of 30% of the blood volume and titration of the mean arterial pressure (MAP) ≈ 40 ± 5 mmHg. Afterwards, the animals received standardized resuscitation including re-transfusion of shed blood, fluids, and, if needed, continuous i.v. noradrenaline to maintain MAP at pre-shock values. Animals were randomly allocated to either receive Na2S2O3 or vehicle control starting 2 hours after initiation of shock until 24 hours of resuscitation. The administration of Na2S2O3 did not alter survival during the observation period of 68 hours after the initiation of shock. No differences in cardio-circulatory functions were noted despite a significantly higher cardiac output, which coincided with significantly more pronounced lactic acidosis at 24 hours of resuscitation in the Na2S2O3 group. Parameters of liver, lung, and kidney function and injury were similar in both groups. However, urine output was significantly higher in the Na2S2O3 group at 24 hours of treatment. Taken together, this study reports no beneficial effect of Na2S2O3 in a clinically relevant model of hemorrhagic shock-and-resuscitation in animals without underlying chronic cardiovascular co-morbidity.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The H2S Donor Sodium Thiosulfate (Na2S2O3) Does Not Improve Inflammation and Organ Damage After Hemorrhagic Shock in Cardiovascular Healthy Swine

Messerer

Gaessler²,

Hoffmann

et al. 2022

Front. Immunol.

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“…We and others have shown that blocking procalcitonin receptor by olcegepant, which is a CRLR/RAMP1 antagonist currently used in migraine treatment research [ 184 ], is a feasible means to ameliorate procalcitonin’s edema-inducing effects, further protects the vascular barrier function and improves murine survival in polymicrobial sepsis [ 173 , 180 ]. However, recent evidence from the evaluation of olcegepant in porcine sepsis suggests that novel pharmacological substances are needed before targeting the procalcitonin/CRLR signaling axis can be moved towards a clinical evaluation [ 185 ]. We dissected that procalcitonin activation depends on truncation by active DPP4, while DPP4 inhibition is able to control procalcitonin effect on the endothelium ( Figure 4 ).…”

Section: Modulation Of Endothelial Permeability During Systemic Infla...mentioning

confidence: 99%

Regulation and Dysregulation of Endothelial Permeability during Systemic Inflammation

Hellenthal

Brabenec

Wagner

2022

Cells

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Systemic inflammation can be triggered by infection, surgery, trauma or burns. During systemic inflammation, an overshooting immune response induces tissue damage resulting in organ dysfunction and mortality. Endothelial cells make up the inner lining of all blood vessels and are critically involved in maintaining organ integrity by regulating tissue perfusion. Permeability of the endothelial monolayer is strictly controlled and highly organ-specific, forming continuous, fenestrated and discontinuous capillaries that orchestrate the extravasation of fluids, proteins and solutes to maintain organ homeostasis. In the physiological state, the endothelial barrier is maintained by the glycocalyx, extracellular matrix and intercellular junctions including adherens and tight junctions. As endothelial cells are constantly sensing and responding to the extracellular environment, their activation by inflammatory stimuli promotes a loss of endothelial barrier function, which has been identified as a hallmark of systemic inflammation, leading to tissue edema formation and hypotension and thus, is a key contributor to lethal outcomes. In this review, we provide a comprehensive summary of the major players, such as the angiopoietin-Tie2 signaling axis, adrenomedullin and vascular endothelial (VE-) cadherin, that substantially contribute to the regulation and dysregulation of endothelial permeability during systemic inflammation and elucidate treatment strategies targeting the preservation of vascular integrity.

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Calcitonin Gene–Related Peptide Monoclonal Antibodies and Risk of SARS-CoV-2 Infection and Severe COVID-19 Outcomes Among Veterans With Migraine Disorder

Wang

Fenton

Deng³

et al. 2023

JAMA Netw Open

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ImportanceCalcitonin gene–related peptide (CGRP), a neuropeptide involved in migraine pathophysiology, is also a key neuroimmune modulator. CGRP antagonists may help mitigate the hyperinflammatory response observed in patients with COVID-19; however, findings from the literature are contradictory, and to date, no study has investigated the safety and effectiveness of CGRP antagonists against COVID-19.ObjectiveTo evaluate the association between CGRP monoclonal antibody (mAb) treatment and risk of SARS-CoV-2 infection and sequela hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death.Design, Setting, and ParticipantsThis retrospective cohort study analyzed the electronic health records of US veterans aged 18 to 65 years who were diagnosed with migraine disorder and were at risk of COVID-19 between January 20, 2020, and May 19, 2022.ExposureInitiation of CGRP mAbs.Main Outcomes and MeasuresThe main outcome was cumulative incidence of SARS-CoV-2 infection. Odds of 30-day hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death were secondary outcomes.ResultsAmong 8 178 652 eligible person-trials (354 294 veterans), 9992 (mean [SD] age, 46.0 [9.5] years; 53.9% male) initiated CGRP mAbs and 8 168 660 (mean [SD] age, 46.6 [10.2] years; 65.7% male) did not initiate CGRP mAbs. Over a 28-month follow-up period, 1247 initiators (12.5%) and 780 575 noninitiators (9.6%) tested positive for SARS-CoV-2. After censoring persons who deviated from treatment, the incidence was 7.4 cases per 1000 person-months among initiators and 6.9 per 1000 person-months among noninitiators. The inverse probability–weighted observational analogs of intention-to-treat and per-protocol hazard ratios were 0.95 (95% CI, 0.89-1.01) and 0.93 (95% CI, 0.86-1.02), respectively. No significant differences in the likelihood of hospitalization (odds ratio [OR], 0.93; 95% CI, 0.62-1.41), requiring supplemental oxygen (OR, 0.77; 95% CI, 0.45-1.30), use of mechanical ventilation (OR, 0.85; 95% CI, 0.26-2.84), or death (OR, 0.67; 95% CI, 0.09-5.23) were observed between CGRP mAb initiators and noninitiators who tested positive for SARS-CoV-2.Conclusions and RelevanceIn this cohort study, CGRP mAb treatment was not associated with positive SARS-CoV-2 test results or risk of severe COVID-19 outcomes, suggesting that CGRP mAbs may be used for migraine prevention during the COVID-19 pandemic. Given the few events of requiring supplemental oxygen, use of mechanical ventilation, and death, replication analysis in a larger sample of patients later in the course of disease is warranted.

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Systemic calcitonin gene-related peptide receptor antagonism decreases survival in a porcine model of polymicrobial sepsis: blinded randomised controlled trial

Cited by 11 publications

References 35 publications

The H2S Donor Sodium Thiosulfate (Na2S2O3) Does Not Improve Inflammation and Organ Damage After Hemorrhagic Shock in Cardiovascular Healthy Swine

The H2S Donor Sodium Thiosulfate (Na2S2O3) Does Not Improve Inflammation and Organ Damage After Hemorrhagic Shock in Cardiovascular Healthy Swine

Regulation and Dysregulation of Endothelial Permeability during Systemic Inflammation

Calcitonin Gene–Related Peptide Monoclonal Antibodies and Risk of SARS-CoV-2 Infection and Severe COVID-19 Outcomes Among Veterans With Migraine Disorder

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