These data suggest that acute effects of MSC therapy in HILI are mainly paracrine mediated; however, optimum long-term improvement following HILI requires treatment with the MSCs themselves or potentially repetitive administration of CM.

Current data suggest that Toll-like receptor 4 (TLR4), a key molecule in the innate immune response, may also be activated following tissue injury. Activation of this receptor is known to induce the production of several proinflammatory cytokines. Given that pulmonary inflammation has been shown to be a key contributor to chronic hypoxia-induced pulmonary vascular remodeling, the authors hypothesized that TLR4-deficient mice would be less susceptible to pulmonary hypertension (PH) as compared to mice with intact TLR4. TLR4-deficient and TLR4-intact strains of inbred mice were exposed to 4, 8, and 16 weeks of hypoxia (0.10 FiO(2)) or normoxia (0.21 FiO(2)) in a normobaric chamber. After chronic hypoxic exposure, TLR4-intact mice developed significant PH evidenced by increased right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery medial thickening. In contrast, TLR4-deficient mice had no significant change in any of these parameters and this was associated with decreased pulmonary vascular inflammatory response as compared to the TLR4-intact mice. These results suggest that TLR4 deficiency may decrease the susceptibility to developing PH by attenuating the pulmonary vascular inflammatory response to chronic hypoxia.

The central excitatory amino acid (EAA) neurotransmitter glutamate has been shown to mediate the ventilatory response to hypoxia through N-methyl-D-aspartate (NMDA) receptors in anesthetized adult animals. To determine the role of the EAA glutamate in the neonatal ventilatory response to hypoxia, 19 unanesthetized chronically instrumented piglets were studied. Minute ventilation (VE), oxygen consumption (VO2), arterial blood pressure (ABP), heart rate (HR), and blood gases were measured in room air (RA) and after 1, 5, and 10 min of hypoxia (inspired oxygen fraction = 0.10) before and after an infusion of saline or CGS-19755, a competitive NMDA-receptor blocker (10 mg/kg i.v.). Nine control piglets [age 6 +/- 1 (SD) days; weight 2.02 +/- 0.40 kg] and 10 CGS-19755-treated animals (age 6 +/- 1 days; weight 1.90 +/- 0.66 kg) were studied during quiet sleep and in a thermoneutral environment. There was a marked decrease in the VE response to hypoxia after the administration of CGS-19755. The ventilatory response to hypoxia was not modified by saline infusion. Changes in ABP and arterial PO2 during hypoxia were similar between groups, whereas the decrease in arterial PCO2 was significantly less after CGS-19755 administration. The increase in HR with hypoxia was eliminated by the NMDA-receptor blocker administration. VO2 decreased with hypoxia in both groups, but this decrease was more marked after the NMDA-receptor blockade. These results suggest that the central EAA glutamate mediates, at least in part, the hypoxic hyperventilation in unanesthetized newborn piglets.

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To determine the effects of endotoxemia on the neonatal ventilatory response to hypoxia, 17 chronically instrumented and unanesthetized newborn piglets (Յ7 d) were studied before and 30 min after the administration of Escherichia coli O55:B5 endotoxin (n ϭ 8) or normal saline (n ϭ 9). Minute ventilation, oxygen consumption, heart rate, arterial blood pressure, and blood gases were measured during normoxia and 10 min of hypoxia (fraction of inspired oxygen, 0.10). Basal ventilation was not modified by E. coli endotoxin infusion (mean Ϯ SE, 516 Ϯ 49 versus 539 Ϯ 56 mL/min/kg), but the ventilatory response to hypoxia was markedly attenuated at 1 min (955 Ϯ 57 versus 718 Ϯ 97 mL/min/kg, p Ͻ 0.002, saline versus endotoxin) and at 10 min (788 Ϯ 51 versus 624 Ϯ 66 mL/min/kg, p Ͻ 0.002). A larger decrease in oxygen consumption was observed during hypoxia and endotoxemia (6.3 Ϯ 2.8 versus 18.3 Ϯ 2.7%, p Ͻ 0.03, pre-versus post-endotoxin). A significant correlation was demonstrated between the changes in minute ventilation and oxygen consumption with hypoxia during endotoxemia (r ϭ 0.9, p Ͻ 0.002). The ventilatory response to hypoxia was not modified by the saline infusion. These data show a significant attenuation in the ventilatory response to hypoxia during E. coli endotoxemia. This decrease in ventilation was associated with a significant decrease in the metabolic rate during hypoxia and endotoxemia. Changes in the breathing pattern and apnea episodes are frequently associated with neonatal sepsis, especially in the preterm infant (1). It has also been observed that the administration of Escherichia coli endotoxin to anesthetized adult cats produced an abrupt apnea followed by transient rapid and shallow breathing (2). However, the mechanisms explaining these changes in breathing pattern are not clearly understood. Respiratory muscle fatigue, a decrease in lung compliance, and an increase in pulmonary resistance have been cited as possible mechanisms for the ventilatory changes observed during Gram-positive and -negative septicemia (3-6).It is well known that a variety of inflammatory mediators such as cytokines, prostaglandins, leukotrienes, and NO are released during sepsis or endotoxemia (3, 6, 7). Furthermore, the changes in the breathing pattern observed during E. coli infusion to adult cats were eliminated in the animals pretreated with indomethacin or thromboxane A 2 receptor antagonist (2). On the other hand, it has been demonstrated that prostaglandins and NO may mediate the ventilatory depression observed during hypoxia in newborn animals (8, 9). Therefore, the increased release of these inflammatory mediators may further depress the ventilatory response to hypoxia during E. coli endotoxemia.The increased circulating cytokines during sepsis or endotoxemia can induce a systemic inflammatory response involving the microvascular system and trigger hemodynamic changes (7, 10, 11). These changes result in maldistribution of blood flow to different organs, which may be accompanied by January 31, 2002; accepted Dec...