Impact of prostaglandin and thromboxane synthesis blockade on disposition of group B streptococcus in lung and liver of intact piglet.

Group B streptococci (GBS) localizing in the lungs of infant piglets is killed in part by an oxygen radical-dependent mechanism (Bowdy BD, Marple SL, Pauly TH, Coonrod JD, Gillespie MN: Am Rev Respir Dis 141:648-653, 1990). The source of bactericidal oxygen radicals is unknown, but cyclooxygenation of arachidonic acid, an initial event in prostanoid synthesis, is accompanied by substantial oxygen radical generation. Because blockade of prostaglandin H synthase (cyclooxygenase) with indomethacin prevents GBS-induced pulmonary hypertension, we reasoned that the salutary effect of indomethacin might be associated with a reduction in the efficacy of bactericidal activity directed against GBS. To address this possibility, the distribution and viability of 111In-labeled GBS (10(8) colony forming units/kg/min i.v. for 15 min) were assessed in lungs and livers of control piglets, piglets treated with indomethacin (1 mg/kg), and piglets treated with OKY-046 (10 mg/kg), an inhibitor of thromboxane synthase that also forestalls GBS-induced pulmonary hypertension. Relative to control animals, indomethacin treatment increased pulmonary GBS uptake with no change in bacterial distribution into the liver. OKY-046 failed to influence pulmonary bacterial uptake but promoted a substantial increase in GBS depositing in the liver. In contrast to its effects on pulmonary bacterial deposition, indomethacin failed to increase lung bacterial viability relative to control animals. Indomethacin also was without effect on hepatic bacterial viability. OKY-046 failed to influence pulmonary bacterial viability but markedly augmented hepatic GBS viability to the extent that significant bacterial proliferation occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Dimethylthiourea reverses sepsis-induced pulmonary hypertension in piglets.

Dimethylthiourea (DMTU), a putative hydroxyl radical scavenger, attenuates thromboxane generation and pulmonary hypertension in the piglet model of group B streptococcal (GBS) sepsis. This study tested the hypothesis that DMTU reverses ongoing GBS-induced pulmonary hypertension coincident with decreased thromboxane production. Piglets (n = 15) received a 60 min infusion of GBS (10(-8) cfu/kg/min). Mean pulmonary artery pressure (Ppa), arterial blood gases (ABGs), and thromboxane B2 (TXB) levels were measured at 10 min intervals throughout the study. GBS infusion resulted in a marked increase in pulmonary artery pressure (mean delta Ppa = 31 mm Hg) and a significant decline in PaO2 (mean = -80 torr) within 10 min of beginning the infusion. pH decreased from a mean of 7.47 to 7.37. DMTU, 750 mg/kg, or normal saline vehicle was infused over 10-15 min beginning 10 min after initiating GBS. Ppa decreased significantly within 10 min of DMTU infusion. Piglets receiving vehicle had a slow decline in Ppa. Piglets receiving DMTU also had an improvement in PaO2 and showed no further drop in pH. Piglets receiving vehicle had no improvement in PaO2 and demonstrated a continued decline in pH. TXB levels did not differ between the groups at any time interval. We conclude that DMTU can partially reverse GBS-induced pulmonary hypertension, but may function through mechanisms independent of thromboxane generation.

Group B streptococcus promotes oxygen radical-dependent thromboxane accumulation in young piglets.

Both thromboxane A2 and oxygen-derived free radicals appear to play central roles in group B streptococcus (GBS)-induced pulmonary hypertension in piglets. This study tested the hypothesis that GBS promotes oxygen radical-dependent thromboxane accumulation and pulmonary hypertension in infant piglets. Piglets 4-12 d old were anesthetized and prepared for assessment of pulmonary arterial pressure and arterial blood gases. In control animals, GBS (10(8) organisms/kg/min for 15 min) increased mean pulmonary artery pressure by 30 +/- 1.5 torr and reduced arterial PO2 by 100 +/- 20 torr. Thromboxane A2, radioimmunoassayed in venous blood as thromboxane B2, increased by 2452 +/- 800 pg/mL. A second group of piglets was treated with dimethylthiourea (DMTU: 750 mg/kg), a putative oxygen radical scavenger. In these animals, GBS increased pulmonary arterial pressure by only 7 +/- 1 torr and reduced arterial PO2 by a modest 10 +/- 8 torr. Importantly, thromboxane B2 content in venous blood failed to increase above control levels in DMTU-treated animals. The protective effects of DMTU in GBS-treated piglets could not be ascribed to inhibition of cyclooxygenase or thromboxane synthase because the oxygen radical scavenger failed to attenuate increases in pulmonary arterial pressure and venous thromboxane B2 content or reductions in arterial PO2 caused by i.v. infusions of arachidonic acid. DMTU also did not ameliorate pulmonary hypertension evoked by the thromboxane mimetic U44069, thereby suggesting that the scavenger did not act as an end-organ antagonist of thromboxane receptors. These observations suggest that GBS promotes accumulation of thromboxane A2 and attendant pulmonary hypertension through an oxygen radical-dependent mechanism.