Roles of Platelet-Activating Factor and Thromboxane in Group B Streptococcus-Induced Pulmonary Hypertension in Piglets

Pinheiro, Joaquim; Pitt, Bruce R.; Gillis, Chris

doi:10.1203/00006450-198911000-00011

Cited by 16 publications

(7 citation statements)

References 28 publications

(40 reference statements)

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“…In many LPS lungs, target flows were not achieved. The increase in PVR during the ex-vivo phase can be explained by sustained vasoconstriction caused by prolonged action of endothelin, thromboxane and platelet activating factor 18,19 . The net effect of this generalized vasoconstriction in the lungs in the LPS group culminated in hypoxia of cells and deterioration of lung metabolism.…”

Section: Discussionmentioning

confidence: 99%

Porcine model of sepsis-induced systemic inflammation and acute lung injury in donor lungs

Nasir

Ménaouar²,

Landry³

et al. 2020

Preprint

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Background: The shortage of organ donors is a major challenge in lung transplantation. To expand the lung donor pool, ex-vivo lung perfusion (EVLP) has emerged as a platform for assessment and reconditioning marginal donor lungs. In this study a stable and reproducible large animal model of lipopolysaccharide (LPS) induced systemic inflammation and acute lung injury (ALI) was developed.Methods: Pigs (n=6) were anesthetized and monitored. After infusion of LPS (20 μg/kg) for 1 hour, followed by a 90-minute response period, lungs were procured and kept on ice for 2 hours, followed by 4 hours of EVLP. Pulmonary function, inflammatory biomarkers and edema formation were measured in vivo before procurement and during EVLP. Pro and anti-inflammatory cytokines were assayed in blood and in EVLP perfusate, which were collected before and every 30 minutes after LPS administration and EVLP.Results: LPS infusion resulted in significant hemodynamic instability, characterized by marked pulmonary hypertension, decreased systemic blood pressure and increased heart rate. This was associated with increased levels of TNFα, IL-10, IL-6, but no change in IL-1β. Ex vivo assessment of injured lungs showed graft dysfunction characterized by impaired gas exchange and edema formation. The inflammatory profile showed stable but elevated TNFα levels, and continuous production of interleukins during EVLP.Conclusion: We describe a reproducible large animal model of LPS-induced systemic inflammation and ALI. EVLP alone was unable to recondition severely injured lungs. These findings suggest that the EVLP platform requires adjuncts such as targeted anti-inflammatory agents to allow reconditioning of marginal donor lungs.

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Section: Discussionmentioning

confidence: 99%

Porcine model of sepsis-induced systemic inflammation and acute lung injury in donor lungs

Nasir

Ménaouar²,

Landry³

et al. 2020

Preprint

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“…8,9,24,25 Pulmonary hypertension has been linked to generation of the arachidonic acid metabolite TXA2 ' and selective TXA2 synthesis inhibitors as well as cyclooxygenase inhibitors have been shown to ameliorate these sequelae. 24,25,27,28 Another mediator implicated in the pathogenesis of these septic syndromes is TNF. The importance of TNF in septic shock has been shown using neutralizing antibodies against TNF that prevent endotoxic shock and in art sepsis sequelae due to Gram-negative bacteremia.…”

Section: Pretreatment With Gbs or Rtnfamentioning

confidence: 99%

Cross-tolerance between bacterial endotoxin and group B Streptococcus in neonatal rats

Mancuso

Blandino

Cusumano

et al. 1994

Journal of Endotoxin Research

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Although endotoxin tolerance can be induced in newborns, potential cross-tolerance to group B Streptococcus (GBS), a common Gram-positive neonatal pathogen has not been investigated. In the present study we tested the hypothesis that endotoxin or recombinant tumor necrosis factor (rTNFα) can induce tolerance to lethal injection of heat-killed GBS in rat newborn pups and vice versa. The effect of such cross-tolerance on endogenous generation of plasma TNFα was subsequently evaluated. Rat pups (18-24 h old) were pretreated intracardially (i.c.) with either phosphate buffered saline (PBS), Salmonella enteritidis endotoxin (30 μg/kg) or rTNFα (35, 70 or 140 μg/kg). The pups were pretreated for either 4, 24, 48, 96 or 240 h prior to a lethal heat-killed GBS challenge. The susceptibility of the neonates to GBS-induced mortality was dependent on the duration of the pretreatment period. At 4 h of pretreatment with endotoxin or TNF, GBS-induced mortality was augmented relative to the PBS group. However, by 24-48 h the endotoxin and TNF pretreated neonates became more resistant to GBS-induced mortality. In a converse of the above experiment, neonates were pretreated with heat killed GBS (0.7 mg/kg) or rTNFα (70 μg/kg) and sensitivity to endotoxin was determined at 4-240 h after pretreatment. The data were qualitatively similar to endotoxin pretreatment. The 4 h GBS or TNF pretreatment rendered the neonates more susceptible to endotoxin-induced mortality. However, by 24-48 h the pretreatment groups were more resistant (P < 0.05) to endotoxin than the PBS controls. Plasma TNFα levels were increased (P < 0.05) 2 h after challenge i.c. with lethal heat-killed GBS or S. enteritidis endotoxin. In the 4 h pretreatment groups that received either GBS or endotoxin and then challenged with endotoxin or GBS, respectively, the plasma TNFα response was markedly augmented (P < 0.05). By 48 h of pretreatment, however, the plasma TNFα response in these groups to the stimuli was significantly reduced (P < 0.05) compared to the PBS pretreated groups. Therefore, plasma TNFα parallels lethality induced by GBS or endotoxin pretreatment. The ability of GBS and endotoxin to induce cross tolerance suggests that common pathophysiological pathways are involved in these syndromes.

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“…Thromboxane seems to play a major role in sepsis. In experimentally induced streptococcal infections it was observed that cycloxygenase inhibitors, such as indomethacin, can prevent pulmonary hypertension [ 34 ]. Recent studies have revealed that vasoconstriction can also be determined by some phospholipids (in particular, phosphatidyl-glycerol and cardiolipin) present in the bacterial wall of streptococcus B [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular physiopathogenetic mechanisms and development of new potential therapeutic strategies in persistent pulmonary hypertension of the newborn

Distefano

Sciacca

2015

Ital J Pediatr

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Persistent pulmonary hypertension of the newborn (PPHN) is a cyanogenic plurifactorial disorder characterized by failed postnatal drop of pulmonary vascular resistance and maintenance of right-to-left shunt across ductus arteriosus and foramen ovale typical of intrauterine life. The pathogenesis of PPHN is very complex and can result from functional (vasoconstriction) or structural (arteriolar remodeling, reduced pulmonary vessels density) anomalies of pulmonary circulation. Etiopathogenetic factors heterogeneity can strongly condition therapeutical results and prognosis of PPHN that is particularly severe in organic forms that are usually refractory to selective pulmonary vasodilator therapy with inhaled nitric oxide. This paper reports the more recent acquisitions on molecular physiopathogenetic mechanisms underlying functional and structural forms of PPHN and illustrates the bases for adoption of new potential treatment strategies for organic PPHN. These strategies aim to reverse pulmonary vascular remodeling in PPHN with arteriolar smooth muscle hypertrophy and stimulate pulmonary vascular and alveolar growth in PPHN associated with lung hypoplasia.In order to restore lung growth in this severe form of PPHN, attention is focused on the results of studies of mesenchymal stem cells and their therapeutical paracrine effects on bronchopulmonry dysplasia, a chronic neonatal lung disease characterized by arrested vascular and alveolar growth and development of pulmonary hypertension.

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Roles of Platelet-Activating Factor and Thromboxane in Group B Streptococcus-Induced Pulmonary Hypertension in Piglets

Cited by 16 publications

References 28 publications

Porcine model of sepsis-induced systemic inflammation and acute lung injury in donor lungs

Porcine model of sepsis-induced systemic inflammation and acute lung injury in donor lungs

Cross-tolerance between bacterial endotoxin and group B Streptococcus in neonatal rats

Molecular physiopathogenetic mechanisms and development of new potential therapeutic strategies in persistent pulmonary hypertension of the newborn

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