Effects of a Leukotriene Antagonist on the Early Hemodynamic Manifestations of Group B Streptococcal Sepsis in Piglets

Goldberg, Ronald N.; Suguihara, Cleide; Streitfeld, Murray M.; Bancalari, Aldo; Clark, Martin R.; Bancalari, Eduardo

doi:10.1203/00006450-198610000-00023

Cited by 27 publications

(17 citation statements)

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“…In isolated piglet lungs perfused at a population of marginated neutrophils, a phagocytic cell known constant flow rate with blood-free physiologic salt solution, to elaborate various mediators incriminated in the response to GBS (lo6 to 10' organisms/mL) provoked concentration-GBS (I), including thromboxane AZ, sulfidopeptide leukotrienes, dependent increases in pulmonary vascular resistance. and toxic oxygen radicals (2)(3)(4). Pulmonary vascular endothelial Transmission electron microscopic examination of isolated cells also exhibit phagocytic activity ( 5 , 6) and produce eicosalungs indicated that GBS was localized within pulmonary noids with chemoattractant activity for neutrophils (7).…”

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confidence: 99%

Organ-Specific Disposition of Group B Streptococci in Piglets: Evidence for a Direct Interaction with Target Cells in the Pulmonary Circulation

Aziz

et al. 1990

Pediatr Res

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ABSTRACT. Despite the serious pulmonary manifestaintact animal could be initiated by a direct interaction tions of early onset group B streptococcal (GBS) sepsis, it between GBS and resident lung cells without obligatory is not known whether the organism distributes into lung participation by other organ systems. (Pediatr Res 27: tissue and whether adverse pulmonary hemodynamic ab-344-348,1990) normalities relate to an interaction between the organism and target cells in the pulmonary vascular bed. AccordAbbreviations ingly, this study evaluated the distribution and fate of GBS in the lung, liver, and spleen of anesthetized infant piglets GBS, group B streptococcus and in isolated, salt solution-perfused piglet lung prepara-HBSS, Hanks' balanced salt solution tions. GBS were radiolabeled with lllIndium-oxine and cfu, colony-forming unit infused at a dose of 108 organisms/kg/min for 15 min into Ppa, pulmonary arterial pressure anesthetized piglets ranging in age from 5-10 d. Forty-five Pla, left atrial pressure min after termination of the infusion, animals were killed Rt, total resistance and specimens of lung, liver, spleen, and blood were excised Ra, arterial resistance and the relative deposition and viability of GBS were Rv, venous resistance determined. Most of the recovered bacteria were detected Pdo, double occlusion pressure in the lung (53.2 f 3.9%) followed by the liver (41.4 f 2.0%) and spleen (2.2 f 0.38%). GBS detected in the blood was estimated to be only 3.2 2 1.0% of the infused dose. Viability of GBS was least in the lung (21.4 2 2.6%)The question is straight-forward: Does GBS promote pulmorelative to the liver (45.7 f 11.2%) and spleen (83.4 +: nary hypertension in the newborn through interaction with a 19.5%). After a 60-min GBS infusion, transmission elec-target cell in the lung? The concept that GBS-induced pulmonary tron microscopy localized the organism within pulmonary hypertension results from an interaction with resident lung cells intravascular macrophages in the lung; there was no evi-is intuitively appealing. The lung contains several cell types that dence for bacterial interaction with either neutrophils or could serve as transducers of the pulmonary hemodynamic reendothelial cells. In the liver, GBS was found exclusively sponse to GBS. For example, the lung contains a substantial in Kupffer cells. In isolated piglet lungs perfused at a population of marginated neutrophils, a phagocytic cell known constant flow rate with blood-free physiologic salt solution, to elaborate various mediators incriminated in the response to GBS (lo6 to 10' organisms/mL) provoked concentration-GBS (I), including thromboxane AZ, sulfidopeptide leukotrienes, dependent increases in pulmonary vascular resistance. and toxic oxygen radicals (2-4). Pulmonary vascular endothelial Transmission electron microscopic examination of isolated cells also exhibit phagocytic activity ( 5 , 6) and produce eicosalungs indicated that GBS was localized within pulmonary noids with chemoattractant activity for neutrophils (7)....

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confidence: 99%

Organ-Specific Disposition of Group B Streptococci in Piglets: Evidence for a Direct Interaction with Target Cells in the Pulmonary Circulation

Aziz

et al. 1990

Pediatr Res

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“…The neonatal pig has been used extensively as a model for pulmonary vascular development and disease (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) because the postnatal morphometric pulmonary development closely parallels the human but on a more compact time scale (14). Typically, pulmonary arterial pressure and flow have been measured during conditions that mimic certain aspects of pulmonary vascular disease (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), such as alveolar hypoxia. The pressure and flow data alone provide an incomplete picture of the pulmonary vascular response.…”

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The Vascular Site of Action of Hypoxia in the Neonatal Pig Lung

et al. 1994

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ABSTRAm. To determine the vascular site(s) of action of hypoxia in the neonatal pig, isolated lungs were perfused at a constant flow rate and left atrial pressure; arterial, venous, and double occlusions were performed. The distribution of the total pulmonary vascular resistance and the total dynamic vascular compliance were calculated using a model of the pulmonary circulation consisting of upstream, central, and downstream compliances and resistances upstream and downstream of central compliance. In addition, the static vascular compliance was measured by venous followed by arterial occlusion, and the total vascular volume was measured by dyedilution. In this preparation during control conditions alveolar Po2 = 12 + 2 kPa), total pulmonary vascular resistance was nearly evenly divided between resistance upstream and downstream of double occlusion pressure and total dynamic vascular compliance was concentrated mainly in the central compliance (7% upstream compliance, 8290 central compliance, and 11 % downstream compliance). Hypoxia (alveolar Po2 = 4 + 1 kPa) increased both resistance upstream of double occlusion pressure ( p < 0.005) and resistance downstream of double occlusion pressure ( p < 0.02) and decreased central compliance (p < 0.005). Hypoxia also decreased total pulmonary blood volume ( p < 0.02). These results suggest that in the pulmonary vasculature of the neonatal pig, hypoxia results mainly in I) arterial constriction as evidenced by a large increase in upstream resistance and a decrease in total pulmonary blood volume and 2) a smaller but significant venous constriction. This venous constriction may have implications in the pathogenesis and therapy of pulmonary vascular diseases associated with hypoxia such as postasphyxial lung disease and bronchopulmonary dysplasia. (Pediarr Res 35: 25-29, 1994 The neonate is at a high risk for pulmonary vascular diseases that manifest increased pulmonary vascular resistance such as persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia, and certain forms of congenital heart disease (1). The neonatal pig has been used extensively as a model for pulmonary vascular development and disease (2-14) because the postnatal morphometric pulmonary development closely parallels the human but on a more compact time scale (14). Typically, pulmonary arterial pressure and flow have been measured during conditions that mimic certain aspects of pulmonary vascular disease (3-14), such as alveolar hypoxia. The pressure and flow data alone provide an incomplete picture of the pulmonary vascular response. For example, the arterial and/or venous site of action may be important in determining the impact on cardiopulmonary function. In the adult, it has been shown that hypoxia causes arterial constriction (1 5-2 1 ), which implies a risk for right ventricular failure, but not necessarily for pulmonary edema because capillary pressure would not be affected. On the other hand, in the neonatal pig (2) and lamb (22) there is some evidence that the pulmonary veins m...

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“…Prior work using models of GBS infusion had found contributions of TxA2 and leukotrienes to the early pulmonary hypertension in GBS sepsis (5,7,11). There is now evidence that in the newborn piglet PAF administration causes pulmonary hypertension, which is to a large extent TxA2 mediated (35).…”

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confidence: 98%

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

1989

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ABSTRACT. Platelet-activating factor causes pulmonary hypertension, shock, hypoxemia, neutropenia, and increased pulmonary vascular permeability; some of its effects are due to thromboxane Az release. Evidence for a possible role of these mediators in the genesis of group B Streptococcus (GBS)-induced pulmonary hypertension was sought using specific receptor antagonists for PAF and thromboxane Az (TxA2) in anesthetized, ventilated piglets (5 12 d of age; n = 22). Infusion of 1 x 10' GBS/kg/min for one hour resulted in a sustained and significant increase in pulmonary artery pressure (PpA) from 17 & 1 to 35 2 3 torr. Pretreatment with the TxA2 antagonist S Q 29548 (0.75 mg/kg intravenous), completely inhibited the effect of GBS on PpA. Pretreatment with either platelet-activating factor antagonists SRI 63072 (3 mg/kg intravenous) or SRI 63441 (1 mg/kg) did not affect the pulmonary hypertension due to GBS infusion. GBS-induced pulmonary hypertension could be reversed by S Q 29548; SRI 63072 did not affect PpA when administered to pigs with GBS-induced elevation in PpA. Inasmuch as prevention and reversal of GBS-induced pulmonary hypertension are accomplished with the TxAz antagonist but not with PAF antagonists, these data suggest that TxA2, rather than PAF, is responsible for the early pulmonary hypertension in this model of neonatal GBS sepsis. Therefore, TxA2 antagonists may be clinically useful in treating pulmonary hypertension related to GBS sepsis. (Pediatr Res 26: 420-424, 1989) Abbreviations GBS, group B Streptococcus SHETE, 5-hydroxyeicosatetraenoic acid PAF, platelet-activating factor PpA, pulmonary artery pressure TxA2, thromboxane AzIn the human neonate, GBS septicemia is associated with pulmonary hypertension, shock, hypoxemia, granulocytopenia, and a high mortality rate, despite antibiotic therapy (1). The pathophysiology of the clinical syndrome has been reproduced in animal models by infusion of live or heat-killed GBS or its endotoxins (2-4). Inflammatory mediators implicated in the early phase responses to endotoxemia (pulmonary hypertension Received March 14, 1988; accepted June 13, 1989. Correspondence Dr. Bruce R. Pitt, Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 1526 1.Supported in part by NIH Grant HL-32154 and HL-13315, as well as postdoctoral training support Grant HL-07410. This work was done during the tenure of B.R.P. as an Established Investigator of the American Heart Assocation. and hypoxemia) include cyclooxygenase products [TxA2 (5-9)], and leukotrienes (1 1). Lipoxygenase products [5-HETE, 12-HETE, leukotrienes C4 and D4 (lo)] may also play a role in the pathogenesis of the late phase pulmonary vascular injury and increased permeability. TxA2 and leukocytes appear to be important mediators of the pulmonary dysfunction induced by GBS toxin in lambs (33).PAF is an autocoid phospholipid mediator with a basic structure of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine. Its cellular sources include endothelial cells, platelets, neutrop...

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Effects of a Leukotriene Antagonist on the Early Hemodynamic Manifestations of Group B Streptococcal Sepsis in Piglets

Cited by 27 publications

References 19 publications

Organ-Specific Disposition of Group B Streptococci in Piglets: Evidence for a Direct Interaction with Target Cells in the Pulmonary Circulation

Organ-Specific Disposition of Group B Streptococci in Piglets: Evidence for a Direct Interaction with Target Cells in the Pulmonary Circulation

The Vascular Site of Action of Hypoxia in the Neonatal Pig Lung

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

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