scholarly journals Apelin-13 in septic shock: effective in supporting hemodynamics in sheep but compromised by enzymatic breakdown in patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David Coquerel ◽  
Julie Lamoureux ◽  
Frédéric Chagnon ◽  
Kien Trân ◽  
Michael Sage ◽  
...  
Keyword(s):  
Septic Shock ◽  
Time Course ◽  
Therapeutic Potential ◽  
Systemic Infection ◽  
Early Time ◽  
Large Animal ◽  
Human Sepsis ◽  
Enzymatic Systems ◽  
Threatening Condition ◽  
Organ Failures

AbstractSepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

Targeting Platelets Containing Electro-encapsulated lloprost to Balloon Injured Aorta in Rats

1995 ◽  
Vol 73 (03) ◽  
pp. 535-542 ◽  
Author(s):  
N Crawford ◽  
A Chajara ◽  
G Pfliegler ◽  
B EI Gamal ◽  
L Brewer ◽  
...  
Keyword(s):  
Time Course ◽  
Therapeutic Potential ◽  
Simple Procedure ◽  
Rat Aorta ◽  
Balloon Injury ◽  
Post Injury ◽  
Antiproliferative Effects ◽  
Platelet Deposition ◽  
Total Dna ◽  
Novel Drug

SummaryDrugs can be electro-encapsulated within platelets and targeted to damaged blood vessels by exploiting the platelet’s natural haemostatic properties to adhere to collagen and other vessel wall constituents revealed by injury. A rat aorta balloon angioplasty model has been used to study the effect on platelet deposition of giving iloprost loaded platelets i.v. during the balloon injury. After labelling the circulating platelets with 111-Indium before balloon injury, time course studies showed maximum platelet deposition on the injured aorta occurred at about 1 h post-injury and the deposition remained stable over the next 2-3 h. When iloprost-loaded platelets were given i.v. during injury and the circulating platelet pool labelled with 111-Indium 30 min later, platelet deposition, measured at 2 h postinjury, was substantially and significantly reduced compared with control platelet treatment. Some antiproliferative effects of iloprost-loaded platelets given i.v. during injury have also been observed. Whereas the incorporation of [3H]-thymidine into aorta intima-media DNA at 3 days post injury was 62-fold higher in balloon injured rats than in control sham operated rats, thymidine incorporation into intima/media of rats which had received iloprost loaded platelets during injury was reduced as compared with rats subjected only to the injury procedure. The reduction was only of near significance, however, but at 14 days after injury the total DNA content of the aorta intima/media of rats given iloprost loaded platelets during injury was significantly reduced. Although iloprost loaded platelets can clearly inhibit excessive platelet deposition, other encapsulated agents may have greater anti-proliferative effects. These studies have shown that drug loaded platelets can be targeted to injured arteries, where they may be retained as depots for local release. We believe this novel drug delivery protocol may have therapeutic potential in reducing the incidence of occlusion and restenosis after angioplasty and thrombolysis treatment. Electro-encapsulation of drugs into platelets is a simple procedure and, using autologous and fully biocompatible and biodegradable platelets as delivery vehicles, might overcome some of the immunological and toxicological problems which have been encountered with other delivery vectors such as liposomes, microbeads, synthetic microcapsules and antibodies.

Synergistic Therapeutic Potential of Dexamethasone and l-arginine in Lipopolysaccharide-Induced Septic Shock

2007 ◽  
Vol 140 (1) ◽  
pp. 99-108 ◽  
Author(s):  
Saurabh Chatterjee ◽  
Sudha Premachandran ◽  
Jyoti Shukla ◽  
T.B. Poduval
Keyword(s):  
Septic Shock ◽  
Therapeutic Potential

scholarly journals Targeting necroptosis as therapeutic potential in chronic myocardial infarction

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Chanon Piamsiri ◽  
Chayodom Maneechote ◽  
Natthaphat Siri-Angkul ◽  
Siriporn C. Chattipakorn ◽  
Nipon Chattipakorn
Keyword(s):  
Myocardial Infarction ◽  
Therapeutic Potential ◽  
Coronary Perfusion ◽  
Beneficial Effects ◽  
Cell Death Pathways ◽  
Threatening Condition ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

AbstractCardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

Perception and first defense responses against Pseudomonas syringae pv. phaseolicola in Phaseolus vulgaris L.: identification of Wall-Associated Kinase receptors

2021 ◽  
Author(s):  
Alfonso Gonzalo De la Rubia ◽  
María Luz Centeno ◽  
Victor Moreno-González ◽  
María De Castro ◽  
Penélope García-Angulo
Keyword(s):  
Phaseolus Vulgaris ◽  
Pseudomonas Syringae ◽  
Time Course ◽  
Early Time ◽  
Experimental System ◽  
Antioxidant Response ◽  
Defense Responses ◽  
Cellular Damage ◽  
Initial Increase ◽  
Phaseolus Vulgaris L

Common bean (Phaseolus vulgaris L.) is attacked by several pathogens such as the biotrophic gamma-proteobacterium Pseudomonas syringae pv. phaseolicola (Pph). In order to study the Pph-bean interaction during the first stages of infection, leaf disks of a susceptible bean variety named Riñón were infected with a pathogenic Pph. Using this experimental system, six new putative Wall-Associated Kinase (WAKs) receptors, previously identified in silico, were tested. These six bean WAKs (PvWAKs) showed high protein sequence homology to the well-described Arabidopsis WAK1 (AtWAK1) receptor and, by phylogenetic analysis, clustered together with AtWAKs. The expression of PvWAK1 increased at very early stages after the Pph infection. Time course experiments were performed to evaluate the accumulation of apoplastic H2O2, Ca2+ influx, total H2O2, antioxidant enzymatic activities, lipid peroxidation, and the concentrations of abscisic acid (ABA) and salicylic acid (SA), as well as the expression of six defense-related genes – MEKK-1, MAPKK, WRKY33, RIN4, PR1 and NPR1. The results showed that overexpression of PR1 occurred 2 h after Pph infection without a concomitant increase in SA levels. Although apoplastic H2O2 increased after infection, the oxidative burst was neither intense nor rapid and an efficient antioxidant response did not occur, suggesting that the observed cellular damage was due to the initial increase in total H2O2 at early time points after infection. In conclusion, the Riñón variety can perceive the presence of Pph, but this recognition only results in a modest and slow activation of host defenses, leading to high susceptibility to Pph.

Early time course of myocardial electrical impedance during acute coronary artery occlusion in pigs, dogs, and humans

2005 ◽  
Vol 99 (4) ◽  
pp. 1576-1581 ◽  
Author(s):  
Carlos L. del Rio ◽  
Patrick I. McConnell ◽  
Bradley D. Clymer ◽  
Roger Dzwonczyk ◽  
Robert E. Michler ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Time Course ◽  
Electrical Impedance ◽  
Early Time ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Acute Ischemia ◽  
Collateral Flow ◽  
Total Occlusion ◽  
Interspecies Differences

Changes in myocardial electrical impedance (MEI) and physiological end points have been correlated during acute ischemia. However, the importance of MEI's early time course is not clear. This study evaluates such significance, by comparing the temporal behavior of MEI during acute total occlusion of the left anterior descending coronary artery in anesthetized humans, dogs, and pigs. Here, interspecies differences in three MEI parameters (baseline, time to plateau onset, and plateau value normalized by baseline) were evaluated using Kruskal-Wallis ANOVA and post hoc tests ( P < 0.05). Noteworthy differences in the MEI time to plateau onset were observed: In dogs, MEI ischemic plateau was reached after 46.3 min (SD 12.9) min of occlusion, a significantly longer period compared with that of pigs and humans [4.7 (SD 1.2) and 4.1 min (SD 1.9), respectively]. However, no differences could be observed between both animal species regarding the normalized MEI ischemic plateau value (15.3% (SD 4.7) in pigs, vs. 19.6% (SD 2.6) in dogs). For all studied MEI parameters, only swine values resembled those of humans. The severity of myocardial supply ischemia, resulting from coronary artery occlusion, is known to be dependent on collateral flow. Thus, because dogs possess a well-developed collateral system (unlike humans or pigs), they have shown superior resistance to occlusion of a coronary artery. Here, the early MEI time course after left anterior descending coronary artery occlusion, represented by the time required to reach ischemic plateau, was proven to reflect such interspecies differences.

Time course of plasma and pulmonary lymph endothelin-like immunoreactivity during sustained endotoxaemia in chronically instrumented sheep

1991 ◽  
Vol 81 (3) ◽  
pp. 357-365 ◽  
Author(s):  
D. R. Morel ◽  
J. F. Pittet ◽  
K. Gunning ◽  
A. Hemsen ◽  
J. S. Lacroix ◽  
...  
Keyword(s):  
Septic Shock ◽  
Organ Failure ◽  
Thoracic Duct ◽  
Time Course ◽  
Reversed Phase ◽  
Left Ventricular ◽  
Endotoxin Infusion ◽  
Endothelin 1 ◽  
Multi Organ Failure ◽  
Conscious Sheep

1. Endothelin, a novel vasoconstrictor 21-residue peptide isolated from the supernatant of cultured porcine endothelial cells, has been shown to be increased in plasma in a variety of cardiovascular disease states, including acute myocardial infarction, acute renal failure and essential hypertension. We determined the time course of plasma and pulmonary lymph endothelin-like immunoreactivity in relation to the progressive deterioration of cardiopulmonary function in an ovine septic shock model leading to multi-organ failure syndrome and death within 42 h of a continuous intravenous infusion of Escherichia coli endotoxin (40 ng min−1 kg−1). 2. Plasma and pulmonary lymph endothelin-like immunoreactivity were measured by r.i.a. using a specific antiserum raised in rabbits against porcine endothelin-1. Endothelin-like immunoreactivity was further determined in lung tissue and the thoracic duct lymph of endotoxin-treated sheep by reversed-phase h.p.l.c. In control instrumented conscious sheep not infused with endotoxin, there were no significant changes in any of the measured cardiopulmonary and biochemical variables, with plasma and pulmonary lymph endothelin-like immunoreactivity remaining below the detection limit (< 1 pg/tube) throughout the 72 h study period. 3. Conscious sheep receiving endotoxin showed a major hypotensive septic syndrome, including persistently decreased systemic blood pressure, systemic vascular resistance, stroke volume, left ventricular stroke work, associated with sustained pulmonary vasoconstriction and protein-rich pulmonary oedema (> five-fold increase in pulmonary lymph flow and protein clearance), and marked lactic acidosis, leading to the death of animals within 14–42 h despite institution of mechanical ventilation and adequate intravascular volume replacement. 4. Appearance of endothelin-like immunoreactivity, as revealed by r.i.a., in arterial plasma and pulmonary lymph was simultaneous in both circulatory beds, with peak values measured between 4 and 12 h after the start of endotoxin infusion (plasma: 68 ± 8 pg/ml, pulmonary lymph: 88 ± 18 pg/ml, P < 0.05 compared with control sheep). After 12 h of endotoxaemia, endothelin-like immunoreactivity in both fluids progressively decreased up to the death of the animals, although remaining significantly above that measured in control sheep. The analysis of extracts of lung and thoracic duct by reversed-phase h.p.l.c. revealed that the r.i.a. method used in the present study mainly detected endothelin-1. 5. Our results demonstrate the presence of a marked and persistent increase in endothelin-like immunoreactivity in plasma and pulmonary lymph of sheep during lethal endotoxin shock with multi-organ failure, suggesting a continuous production and/or release of endothelin-1 into the pulmonary lymph and the systemic circulation upon continuous endotoxin infusion. These findings suggest that endothelin may contribute to the vasomotor disturbances observed during the development of septic shock, although studies using selective receptor antagonists or synthesis inhibitors are required to definitively confirm a potential pathophysiological role of endothelin during endotoxaemia.

scholarly journals Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study

2011 ◽  
Vol 9 (1) ◽  
pp. 23 ◽  
Author(s):  
Brunna E Alves ◽  
Silmara AL Montalvao ◽  
Francisco JP Aranha ◽  
Irene Lorand-Metze ◽  
Carmino A De Souza ◽  
...  
Keyword(s):  
Septic Shock ◽  
Prospective Study ◽  
Time Course ◽  
Neutropenic Patients ◽  
Sepsis And Septic Shock ◽  
A Prospective Study

scholarly journals Making the Most of the Host; Targeting the Autophagy Pathway Facilitates Staphylococcus aureus Intracellular Survival in Neutrophils

2021 ◽  
Vol 12 ◽  
Author(s):  
Emilio G. Vozza ◽  
Michelle E. Mulcahy ◽  
Rachel M. McLoughlin
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Potential ◽  
Systemic Infection ◽  
Opportunistic Pathogen ◽  
Intracellular Survival ◽  
Innate Immune ◽  
Pathogenic Role ◽  
New Host ◽  
Increased Risk ◽  
Autophagy Pathway

The success of Staphylococcus aureus as a human commensal and an opportunistic pathogen relies on its ability to adapt to several niches within the host. The innate immune response plays a key role in protecting the host against S. aureus infection; however, S. aureus adeptness at evading the innate immune system is indisputably evident. The “Trojan horse” theory has been postulated to describe a mechanism by which S. aureus takes advantage of phagocytes as a survival niche within the host to facilitate dissemination of S. aureus to secondary sites during systemic infection. Several studies have determined that S. aureus can parasitize both professional and non-professional phagocytes by manipulating the host autophagy pathway in order to create an intracellular survival niche. Neutrophils represent a critical cell type in S. aureus infection as demonstrated by the increased risk of infection among patients with congenital neutrophil disorders. However, S. aureus has been repeatedly shown to survive intracellularly within neutrophils with evidence now supporting a pathogenic role of host autophagy. By manipulating this pathway, S. aureus can also alter the apoptotic fate of the neutrophil and potentially skew other important signalling pathways for its own gain. Understanding these critical host-pathogen interactions could lead to the development of new host directed therapeutics for the treatment of S. aureus infection by removing its intracellular niche and restoring host bactericidal functions. This review discusses the current findings surrounding intracellular survival of S. aureus within neutrophils, the pathogenic role autophagy plays in this process and considers the therapeutic potential for targeting this immune evasion mechanism.

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