Group B Streptococcal Sepsis in Piglets: Effect of Combined Pentoxifylline and Indomethacin Pretreatment

Abstract

ABSTRACT. Group B streptococcus (GBS), a common neonatal gram-positive pathogen, causes similar pathophysiology in human newborns and neonatal animal models of sepsis. Animal models of GBS sepsis demonstrate a two-phase response: 1 ) an acute phase (<I h) of increased pulmonary artery pressure (P,,) and reduced arterial oxygen pressure (Pao2) that is associated with increased serum thromboxane Bz (TxB2) and 2) a late phase (2-4 h) of persistently increased P,, and reduced Paoz, reduced systemic arterial pressure, and progressive fall in cardiac output that is associated with increased serum TxB2, 6-keto-prostaglandin F1, (6-keto-PGF,,), and tumor necrosis factor-a (TNF,). We hypothesized that pretreatment of piglets with both pentoxifylline (PTF), an inhibitor of TNF, production and activity, and indomethacin (INDO) would 1 ) inhibit GBS-induced TxB2, 6-keto-PGF,,, and TNF, and 2) prevent both the acute-and late-phase physiologic responses of GBS sepsis. Combined PTF and INDO pretreatment of anesthetized, mechanically ventilated piglets infused with GBS (1.25 x lo9 colony forming units/ kglh) for 4 h prevented GBS-induced increases in P,, at 1 h (GBS+PTF+INDO: 1.8 f 0.07 kPa versus GBS alone: 4.7 f 0.1 kPa) and markedly attenuated increases in P,, at 4 h (GBS+PTF+INDO: 2.1 f 0.1 kPa versus GBS alone: 4.4 f 0.1 kPa). PTF+INDO treatment prevented GBS-induced reductions in both mixed venous oxygen pressure and Paoz at 1, 2, and 4 h (GBS+PTF+INDO: 11.5 2 0.4 kPa versus GBS alone: 7.1 f 0.4 kPa), and attenuated GBS-induced declines in .cardiac output. PTF+INDO treatment significantly attenuated GBS-induced serum TNF, polypeptide levels (ELISA, pg/mL) at 4 h (GBS+PTF+INDO: 143 f 45 versus GBS alone: 502 f 147) and blocked GBS-induced increases in serum TxBz and 6-keto-PGR, (all levels < 10 pg1O.l mL by RIA).INDO pretreatment alone prevented GBS-induced increases in serum TxBz and 6-keto-PGF1, levels but did not significantly inhibit GBS-induced TNF, production. INDO pretreatment alone did not attenuate GBS-induced increases in Ppa at 4 h, nor prevent late-phase reductions in both Pao2 and mixed venous oxygen pressure. PTF+INDO treatment of GBS sepsis in piglets is superior to treatment with INDO or PTF alone. Inhibition of both blood eicosanoid and TNF, production may provide adjunctive therapy for human newborns with sepsis and pulmonary hypertension. (Pediatr Res 31: 222-227,1992) Received Abbreviations cfu, colony forming unit CO, cardiac output GBS, group B streptococcus INDO, indomethacin PGI,, prostaglandin Iz 6-keto-PGF,,, 6-keto-prostaglandin F1, P,,, pulmonary artery pressure P,,, systemic arterial pressure PTF, pentoxifylline PVR, pulmonary vascular resistance TNF,, tumor necrosis factor-a TxB2, thromboxane B2 TxA2, thromboxane Az Paoz, arterial oxygen pressure P,, capillary wedge pressure SVR, systemic vascular resistance GBS sepsis in human neonates is associated with hypoxemia, pulmonary hypertension, shock, and high mortality (1-3). Neonatal animal models of i.v. GBS infusion show similar features, bu...

Group B streptococcal phospholipid causes pulmonary hypertension

“…Cyclooxygenase inhibitors such as indomethacin consistently block thromboxane synthesis and the pulmonary hypertensive effect of infused GBS in animals (6,(16)(17)(18)(19). If the bacterial phospholipid is the bioactive molecule of GBS, then indomethacin should also prevent the pulmonary hypertensive response to cardiolipin.…”

Effect of Nitric Oxide Synthase Inhibition during Group B Streptococcal Sepsis in Neonatal Piglets

“…GBS sepsis can produce pulmonary hypertension, reduced cardiac output, hypoxemia, and V~Q mismatch in human neonates and neonatal animals (10)(11)(12). GBS-induced lung vascular injury also occurs as suggested by GBS invasion of lung capillary walls, intraalveolar hemorrhage and proteinrich pulmonary edema in human infants (13,14), and ultrastructural findings of lung capillary endothelial cell injury in both a piglet and nonhuman primate model of GBS sepsis (10,15).…”

“…GBS is a Gram-positive pathogen and the most common cause of neonatal sepsis (10)(11)(12)(13)(14). GBS sepsis can produce pulmonary hypertension, reduced cardiac output, hypoxemia, and V~Q mismatch in human neonates and neonatal animals (10)(11)(12).…”

Induction of cyclooxygenase-2 by human monocytes exposed to group B streptococci

“…Release of the eicosanoids, thromboxane A 2 and prostacyclin, and of TNF-␣ occurs in experimental animals subjected to GBS infection [14,44]. Gibson et al [15] showed that a combination of indomethacin and pentoxifylline, an inhibitor of TNF-␣ production was required to observe a decrease in pulmonary vascular resistance in their animal model of GBS sepsis. These data suggested that a combination of eicosanoids and TNF-␣ were responsible for the increased vascular tone observed in GBS sepsis.…”

“…Rowen and colleagues reported that exposure of human monocytes to GBS induced secretion of leukotriene B 4 [13]. Animal models indicate that additional lipid metabolic products, including the eicosanoids thromboxane A 2 , prostacyclin, and prostaglandin E 2 mediate hemodynamic and other physiological responses in GBS infections [14][15][16][17]. The specific component(s) of GBS and the mechanism(s) responsible for eicosanoid synthesis are not completely understood.…”