Antagonism of stem cell factor/c-kit signaling attenuates neonatal chronic hypoxia-induced pulmonary vascular remodeling.

BACKGROUND: Accumulating evidence suggests that c-kit-positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/c-kit-regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. METHODS: Neonatal FVB/NJ mice treated with nonimmune IgG (placebo), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1-Kit(W-v/+)) and their congenic controls, were exposed to normoxia (FiO2 = 0.21) or hypoxia (FiO2 = 0.12) for 2 wk. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation, and remodeling were evaluated. RESULTS: As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling, and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation, and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. CONCLUSION: SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH.

CXCR4 blockade attenuates hyperoxia-induced lung injury in neonatal rats.

BACKGROUND: Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal-derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. It is not known if antagonism of CXCR4 alleviates lung inflammation in neonatal hyperoxia-induced lung injury. OBJECTIVE: We aimed to determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. METHODS: Newborn rats exposed to normoxia (room air, RA) or hyperoxia (FiO2 = 0.9) from postnatal day 2 (P2) to P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis and inflammation were evaluated at P16. RESULTS: Compared to the RA pups, hyperoxic PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in the macrophage and neutrophil counts in the bronchoalveolar lavage fluid and reduced lung myeloperoxidase activity. CONCLUSION: CXCR4 antagonism decreases lung inflammation and improves alveolar and vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD.

Bone marrow-derived c-kit+ cells attenuate neonatal hyperoxia-induced lung injury.

Recent studies suggest that bone marrow (BM)-derived stem cells have therapeutic efficacy in neonatal hyperoxia-induced lung injury (HILI). c-kit, a tyrosine kinase receptor that regulates angiogenesis, is expressed on several populations of BM-derived cells. Preterm infants exposed to hyperoxia have decreased lung angiogenesis. Here we tested the hypothesis that administration of BM-derived c-kit(+) cells would improve angiogenesis in neonatal rats with HILI. To determine whether intratracheal (IT) administration of BM-derived c-kit(+) cells attenuates neonatal HILI, rat pups exposed to either normobaric normoxia (21% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to P15 were randomly assigned to receive either IT BM-derived green fluorescent protein (GFP)(+) c-kit(-) cells (PL) or BM-derived GFP(+) c-kit(+) cells on P8. The effect of cell therapy on lung angiogenesis, alveolarization, pulmonary hypertension, vascular remodeling, cell proliferation, and apoptosis was determined at P15. Cell engraftment was determined by GFP immunostaining. Compared to PL, the IT administration of BM-derived c-kit(+) cells to neonatal rodents with HILI improved alveolarization as evidenced by increased lung septation and decreased mean linear intercept. This was accompanied by an increase in lung vascular density, a decrease in lung apoptosis, and an increase in the secretion of proangiogenic factors. There was no difference in pulmonary vascular remodeling or the degree of pulmonary hypertension. Confocal microscopy demonstrated that 1% of total lung cells were GFP(+) cells. IT administration of BM-derived c-kit(+) cells improves lung alveolarization and angiogenesis in neonatal HILI, and this may be secondary to an improvement in the lung angiogenic milieu.

Stem cell factor improves lung recovery in rats following neonatal hyperoxia-induced lung injury.

BACKGROUND: Stem cell factor (SCF) and its receptor, c-kit, are modulators of angiogenesis. Neonatal hyperoxia-induced lung injury (HILI) is characterized by disordered angiogenesis. The objective of this study was to determine whether exogenous SCF improves recovery from neonatal HILI by improving angiogenesis. METHODS: Newborn rats assigned to normoxia (RA: 20.9% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to 15, received daily injections of SCF 100 µg/kg or placebo (PL) from P15 to P21. Lung morphometry was performed at P28. Capillary tube formation in SCF-treated hyperoxia-exposed pulmonary microvascular endothelial cells (HPMECs) was determined by Matrigel assay. RESULTS: As compared with RA, hyperoxic-PL pups had decrease in alveolarization and in lung vascular density, and this was associated with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and vascular remodeling. In contrast, SCF-treated hyperoxic pups had increased angiogenesis, improved alveolarization, and attenuation of pulmonary hypertension as evidenced by decreased RVSP, right ventricular hypertrophy, and vascular remodeling. Moreover, in an in vitro model, SCF increased capillary tube formation in hyperoxia-exposed HPMECs. CONCLUSION: Exogenous SCF restores alveolar and vascular structure in neonatal rats with HILI by promoting neoangiogenesis. These findings suggest a new strategy to treat lung diseases characterized by dysangiogenesis.

Long-term reparative effects of mesenchymal stem cell therapy following neonatal hyperoxia-induced lung injury.

BACKGROUND: Mesenchymal stem cell (MSC) therapy may prevent neonatal hyperoxia-induced lung injury (HILI). There are, however, no clear data on the therapeutic efficacy of MSC therapy in established HILI, the duration of the reparative effects, and the exact mechanisms of repair. The main objective of this study was to evaluate whether the long-term reparative effects of a single intratracheal (IT) dose of MSCs or MSC-conditioned medium (CM) are comparable in established HILI. METHODS: Newborn rats exposed to normoxia or hyperoxia from postnatal day (P)2)-P16 were randomized to receive IT MSCs, IT CM, or IT placebo (PL) on P9. Alveolarization and angiogenesis were evaluated at P16, P30, and P100. RESULTS: At all time periods, there were marked improvements in alveolar and vascular development in hyperoxic pups treated with MSCs or CM as compared with PL. This was associated with decreased expression of inflammatory mediators and an upregulation of angiogenic factors. Of note, at P100, the improvements were more substantial with MSCs as compared with CM. CONCLUSION: 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.

Antagonism of CXCR7 attenuates chronic hypoxia-induced pulmonary hypertension.

INTRODUCTION: Chemokines may directly participate in the pathogenesis of neonatal chronic hypoxia-induced pulmonary hypertension (PH). Although stromal-derived factor-1 (SDF-1) has been shown to be involved in PH, the role of its most recently discovered receptor, chemokine receptor type 7 (CXCR7), remains unclear. We sought to determine whether antagonism of the CXCR7 receptor would decrease pulmonary vascular remodeling in newborn mice exposed to chronic hypoxia by decreasing pulmonary vascular cell proliferation. METHODS: Neonatal mice were exposed to hypoxia (fractional inspired oxygen concentration = 0.12) or room air (RA) for 2 wk. After 1 wk of exposure, mice received daily injections of placebo or a CXCR7 antagonist (CCX771) from postnatal day 7 (P7) to P14. Right ventricular systolic pressure (RVSP), the ratio of the weight of the right ventricle to left ventricle + septum (RV/LV + S), and pulmonary vascular cell proliferation and remodeling were determined at P14. RESULTS: As compared with mice exposed to RA, hypoxia placebo mice had a significant increase in the lung protein expression of CXCR7. Although hypoxic placebo-treated mice had a significant increase in RVSP, RV/LV+S, and pulmonary vascular cell proliferation and remodeling, the administration of CCX771 markedly decreased these changes. DISCUSSION: These results indicate that antagonism of CXCR7 may be a potent strategy to decrease PH and vascular remodeling.

Effects of intermittent nebulization of NONOate, DPTA/NO, on group B Streptococcus-induced pulmonary hypertension in newborn piglets.

BACKGROUND: A single dose of NONOate attenuates pulmonary hypertension (PH) induced by group B Streptococcus (GBS) infusion and this is accompanied by a decrease in systemic vascular resistance (SVR). OBJECTIVE: The objective of the study was to determine whether two doses of the NONOate sustain the attenuation in GBS-induced PH without further systemic compromise. METHODS: 15 anesthetized newborn piglets were randomized to receive placebo (n = 8) or two doses of nebulized DPTA/NO (n = 7) at 15 and 75 min after GBS-induced PH. Pulmonary artery (Ppa) and systemic (Psa) pressures, cardiac output (CO) and arterial blood gases were obtained at baseline and every 15 min until 180 min during GBS infusion. RESULTS: Ppa and pulmonary vascular resistance (PVR) decreased significantly after the first dose of nebulized DPTA/NO and this effect was maintained after the second dose. Psa and SVR decreased after the first dose of DPTA/NO to values close to baseline and no further changes in systemic circulation were observed with repeated treatment. PVR/SVR increased with GBS infusion, but decreased after the first dose of DPTA/NO and remained significantly lower for 180 min. CO was significantly higher in the DPTA/NO group. Changes in Ppa, PVR, Psa, SVR, and CO with GBS infusion were not modified by placebo infusion. PaCO(2), base deficit, and pH did not differ between groups. PaO(2) was significantly lower in the DPTA/NO group after the second dose. CONCLUSION: These data demonstrated that GBS-induced PH is attenuated with two doses of DPTA/NO without significant systemic effect. The vasodilatory effect is more pronounced in the pulmonary than in the systemic vasculature, as suggested by lower PVR/SVR in the DPTA/NO group. We speculate that NONOates may have a clinical application in the management of PH in neonates.

Toll-like receptor 4-deficient mice are resistant to chronic hypoxia-induced pulmonary hypertension.

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.

Inhibition of the SDF-1/CXCR4 axis attenuates neonatal hypoxia-induced pulmonary hypertension.

Exposure of the neonatal lung to chronic hypoxia produces significant pulmonary vascular remodeling, right ventricular hypertrophy, and decreased lung alveolarization. Given recent data suggesting that stem cells could contribute to pulmonary vascular remodeling and right ventricular hypertrophy, we tested the hypothesis that blockade of SDF-1 (stromal cell-derived factor 1), a key stem cell mobilizer or its receptor, CXCR4 (CXC chemokine receptor 4), would attenuate and reverse hypoxia-induced cardiopulmonary remodeling in newborn mice. Neonatal mice exposed to normoxia or hypoxia were randomly assigned to receive daily intraperitoneal injections of normal saline, AMD3100, or anti-SDF-1 antibody from postnatal day 1 to 7 (preventive strategy) or postnatal day 7 to 14 (therapeutic strategy). As compared to normal saline, inhibition of the SDF-1/CXCR4 axis significantly improved lung alveolarization and decreased pulmonary hypertension, right ventricular hypertrophy, vascular remodeling, vascular cell proliferation, and lung or right ventricular stem cell expressions to near baseline values. We therefore conclude that the SDF-1/CXCR4 axis both prevents and reverses hypoxia-induced cardiopulmonary remodeling in neonatal mice, by decreasing progenitor cell recruitment to the pulmonary vasculature, as well as by decreasing pulmonary vascular cell proliferation. These data offer novel insights into the role of the SDF-1/CXCR4 axis in the pathogenesis of neonatal hypoxia-induced cardiopulmonary remodeling and have important therapeutic implications.

Targeted minute ventilation and tidal volume in an animal model of acute changes in lung mechanics and episodes of hypoxemia.

BACKGROUND: Acute episodes of hypoxemia in ventilated preterm infants are triggered by changes in ventilation, lung volume (LV) and respiratory system compliance (C(RS)) that are not prevented by conventional synchronized intermittent mandatory ventilation (SIMV). OBJECTIVE: To assess in a rabbit model of episodic hypoxemia the individual and combined efficacy of targeted tidal volume (V(T)) and minute ventilation (V'(E)) by automatic adjustment of peak inspiratory pressure (PIP) and ventilator rate, respectively. METHODS: Six young New Zealand white rabbits were ventilated with SIMV, targeted V(T), targeted V'(E), and combined targeted V'(E) + V(T) in random sequence. Hypoxemia episodes were induced by apnea alone or by apnea combined with a reduction in LV and C(RS). Apnea was induced by a bolus of propofol. The reduction in LV and C(RS) was induced by chest compression with a cuff. PaO(2) and PaCO(2) were measured continuously by an indwelling arterial electrode. RESULTS: During SIMV, apnea caused a decrease in ventilation and PaO(2). This was attenuated during targeted V'(E) and targeted V'(E) + V(T). Apnea plus a reduction in LV and C(RS) caused a greater decrease in ventilation and PaO(2) during SIMV. These changes were attenuated during targeted V(T) and targeted V'(E). The attenuation was more pronounced during targeted V'(E) + V(T). CONCLUSION: In this animal model, targeted V'(E) was effective in reducing hypoxemia caused by apnea. When apnea was accompanied by a reduction in LV and C(RS), the combined adjustment of PIP and ventilator rate was more effective than each individually. This combined strategy may be effective in ameliorating acute episodes of hypoxemia in preterm infants but this remains to be proven.

High tidal volume ventilation activates Smad2 and upregulates expression of connective tissue growth factor in newborn rat lung.

High tidal volume (V(T)) ventilation plays a key role in ventilator induced lung injury and bronchopulmonary dysplasia. However, little is known about the effect of high V(T) on expression of growth factors that are critical to lung development. In a previous study, we demonstrated that connective tissue growth factor (CTGF) inhibits branching morphogenesis. In this study, we investigated the effect of high V(T) on CTGF expression in newborn rat lungs. Newborn rats were ventilated with normal V(T) (10 mL/kg) or high V(T) (25 mL/kg) for 6 h. Nonventilated animals served as controls. We found that high V(T) upregulated CTGF expression. To identify the potential signaling pathways mediating high V(T) induction of CTGF, newborn rats were ventilated with high V(T) for 1 or 3 h. Temporal expression of TGF-betas, p-Smad2, Smad7, and CTGF was analyzed. High V(T) ventilation did not change gene expression of TGF-betas and Smad7 but induced rapid and sustained expression of p-Smad2 that precedes increased CTGF expression. CTGF and p-Smad2 were localized in bronchiolar epithelial cells, alveolar walls and septa. These data suggest that high V(t) ventilation activates the Smad2 pathway, which may be responsible for downstream induction of CTGF expression in newborn rat lungs.

The effect of pentoxifylline on the pulmonary response to high tidal volume ventilation in rats.

BACKGROUND: Volume-induced lung injury is associated with lung inflammation. Pentoxifylline inhibits cytokine release and modulates neutrophil function. OBJECTIVE: To evaluate the efficacy of pentoxifylline in the attenuation of lung inflammation induced by high tidal volume ventilation. DESIGN: Adult rats were randomly assigned to receive saline as placebo or pentoxifylline (100mg/kg over 30 min, followed by 50mg/kg/h) before and during 4h of high tidal volume ventilation (20 ml/kg). Bronchoalveolar fluid inflammatory mediators were measured at baseline and after 4h of ventilation. Lung tissue myeloperoxidase activity and wet/dry lung weight were assessed upon completion of the study. RESULTS: Bronchoalveolar tumor necrosis factor-alpha (pentoxifylline vs. placebo; 192+/-61 vs. 543+/-99 pg/ml; p<0.007) and thromboxane B(2) (262+/-26 vs. 418+/-49 pg/ml; p<0.02) concentrations, lung myeloperoxidase activity (0.5+/-0.1 vs. 1.2+/-0.2U/mg; p<0.003) and wet/dry weight (6.1+/-0.2 vs. 7.1+/-0.3; p<0.01) were all significantly lower in the pentoxifylline-treated group. CONCLUSION: Pentoxifylline was effective in reducing inflammatory lung injury associated with high tidal volume ventilation.

The role of angiotensin II receptor-1 blockade in the hypoxic pulmonary vasoconstriction response in newborn piglets.

BACKGROUND: Angiotensin-converting enzyme activity is increased in newborn infants with respiratory distress syndrome and in animals with alveolar hypoxia. OBJECTIVE: To test whether angiotensin II (Ang II) mediates the pulmonary vasoconstriction induced by acute hypoxia in newborn piglets. METHODS: Eight unanesthetized chronically instrumented newborn piglets (mean +/- SEM; age 6.6 +/- 0.6 days; weight 2,181 +/- 174 g) were randomly assigned to receive a saline solution or the Ang II type 1 receptor (AT(1)) antagonist, losartan, in a crossover study design, with an interval of at least 48 h between the first and second study. Pulmonary artery (Ppa), wedge, systemic arterial (Psa) and right atrial pressures, cardiac output (CO), pulmonary (PVR) and systemic (SVR) vascular resistances, and arterial blood gases were obtained in room air, before and during the saline or losartan infusion (6 mg/kg followed by 3 mg/kg/h), and during 6 h of hypoxia (FiO(2) = 0.11) and saline or losartan infusion. Data were analyzed by repeated measures analysis of variance. RESULTS: The pulmonary vasoconstriction induced by acute hypoxia was significantly attenuated during losartan infusion, while Psa, SVR, CO, pH, PaCO(2), PaO(2) and base excess did not differ between groups. During room air, Ppa, PVR, Psa, SVR and CO values were not modified by saline or losartan infusion. CONCLUSION: These data suggest that the pulmonary vasoconstriction induced by acute hypoxia in newborn piglets is partially mediated by Ang II, acting via AT(1).

Brainstem amino acid neurotransmitters and ventilatory response to hypoxia in piglets.

The ventilatory response to hypoxia is influenced by the balance between inhibitory (GABA, glycine, and taurine) and excitatory (glutamate and aspartate) brainstem amino acid (AA) neurotransmitters. To assess the effects of AA in the nucleus tractus solitarius (NTS) on the ventilatory response to hypoxia at 1 and 2 wk of age, inhibitory and excitatory AA were sampled by microdialysis in unanesthetized and chronically instrumented piglets. Microdialysis samples from the NTS area were collected at 5-min intervals and minute ventilation (VE), arterial blood pressure (ABP), and arterial blood gases (ABG) were measured while the animals were in quiet sleep. A biphasic ventilatory response to hypoxia was observed in wk 1 and 2, but the decrease in VE at 10 and 15 min was more marked in wk 1. This was associated with an increase in inhibitory AA during hypoxia in wk 1. Excitatory AA levels were elevated during hypoxia in wk 1 and 2. Changes in ABP, pH, and ABG during hypoxia were not different between weeks. These data suggest that the larger depression in the ventilatory response to hypoxia observed in younger piglets is mediated by predominance of the inhibitory AA neurotransmitters, GABA, glycine, and taurine, in the NTS.

Ventilatory response to hypoxia during endotoxemia in young rats: role of nitric oxide.

Administration of Escherichia coli endotoxin attenuates the ventilatory response to hypoxia (VRH) in newborn piglets, but the mechanisms responsible for this depression are not clearly understood. Nitric oxide (NO) production increases during sepsis and elevated NO levels can inhibit carotid body function. The role of endothelial NO on the VRH during endotoxemia was evaluated in 26 young rats. Minute ventilation (VE) and oxygen consumption (VO2) were measured in room air (RA) and during 30 min of hypoxia (10% O2) before and after E. coli endotoxin administration. During endotoxemia, animals received placebo (PL, n = 8); a nonselective nitric oxide synthase (NOS) inhibitor (NG-nitro-L-arginine methyl ester, L-NAME, n = 9), or a neuronal NOS (nNOS) inhibitor (7-nitroindazole, 7-NI, n = 9). During endotoxemia, a larger increase in VE was observed only during the first min of hypoxia in the L-NAME group when compared with PL or 7-NI (p < 0.001). VRH was similar in the PL and 7-NI groups. A larger decrease in VO2 at 30 min of hypoxia was observed in L-NAME and 7-NI groups when compared with PL (p < 0.03). These data demonstrate that the attenuation of the early VRH during endotoxemia is in part mediated by an inhibitory effect of endothelial NO on the respiratory control mechanisms.

[Strategies to minimize lung injury in extremely low birth weight infants]. / Como minimizar a lesão pulmonar no prematuro extremo: propostas.

OBJECTIVE: To review the main causes of new bronchopulmonary dysplasia and the strategies utilized to decrease its incidence in extremely low birth weight infants. SOURCES OF DATA: For this review a MEDLINE search from 1966 to October 2004, the Cochrane Database, abstracts from the Society for Pediatric Research and recent meetings on the topic were used. SUMMARY OF THE FINDINGS: The survival of extremely low birth weight infants has increased significantly due to improvement in both scientific knowledge and technology. This improvement in survival has therefore resulted in an increased incidence of bronchopulmonary dysplasia. The characteristics of bronchopulmonary dysplasia in extremely low birth weight infants, the so called "new" bronchopulmonary dysplasia are quite different from the classic bronchopulmonary dysplasia described by Northway. This new bronchopulmonary dysplasia has a multifactorial etiology, which includes volutrauma, atelectrauma, oxygen toxicity and lung inflammation. Therapy such as prenatal corticosteroids, exogenous surfactant, nasal continuous positive airway pressure, new mechanical ventilation modalities and gentle ventilation have been used in attempts to decrease lung injury severity. CONCLUSIONS: In order to prevent lung injury in extremely low birth weight infants, it is necessary to minimize several factors that induce bronchopulmonary dysplasia and to utilize less aggressive therapeutic strategies. In addition to the current therapy used to decrease lung injury, knowledge of these causative factors may create new therapies that may be fundamental in improving the clinical outcomes of premature infants.

Effect of respiratory syncytial virus on apnea in weanling rats.

Apnea is a common complication of respiratory syncytial virus (RSV) infection in young infants. The purpose of this study was to determine whether this infection affects apnea triggered by sensorineural stimulation in weanling rats. We also studied which neurotransmitters are involved in this response and whether passive prophylaxis with a specific neutralizing antibody (palivizumab) confers protection against it. Weanling rats were inoculated intranasally with RSV, adenovirus, or virus-free medium. Changes in respiratory rate and apnea in response to nerve stimulation with increasing doses of capsaicin were measured by plethysmography. Capsaicin-induced apnea was significantly longer in RSV-infected rats at postinoculation days 2 (upper airways infection) and 5 (lower airways infection), and apnea-related mortality occurred only in the RSV-infected group. Reduction in the duration of apnea was observed after selective inhibition of central gamma-aminobutyric acid (GABA) type A receptors and neurokinin type 1 receptors for substance P. Prophylactic palivizumab protected against apnea and apnea-related mortality. These results suggest that sensorineural stimulation during RSV infection is associated with the development of apnea and apnea-related death in early life, whose mechanism involves the release of GABA acting on central GABA type A receptors and substance P acting on neurokinin type 1 receptors.

Como minimizar a lesão pulmonar no prematuro extremo: propostas / Strategies to minimize lung injury in extremely low birth weight infants

OBJETIVO: Apresentar uma revisão das principais causas da nova displasia broncopulmonar e as estratégias utilizadas para diminuir sua incidência nos prematuros extremos. FONTES DOS DADOS: Para essa revisão, pesquisas foram feitas na MEDLINE (1996 a outubro de 2004), no Cochrane Database, em resumos da Society for Pediatric Research e recentes conferências sobre o tema. SíNTESE DOS DADOS: A tecnologia e os novos conhecimentos científicos têm aumentado significantemente a sobrevida de prematuros extremos. Esse aumento da sobrevida resultou em aumento da incidência de displasia broncopulmonar. Atualmente, a displasia broncopulmonar é mais freqüentemente observada em recém-nascidos < 1.200 g. As características da displasia broncopulmonar nesses prematuros extremos, atualmente chamada de "nova" displasia broncopulmonar, são bastante diferentes da clássica descrita por Northway. A nova displasia broncopulmonar tem etiologia multifatorial, como volutrauma, atelectrauma, toxicidade ao oxigênio e reação inflamatória. Terapias como corticosteróide pré-natal, surfactante exógeno, pressão aérea positiva contínua nasal, novos tipos de ventilação mecânica e uma ventilação mais gentil têm sido usadas para tentar diminuir a gravidade da lesão pulmonar. CONCLUSÕES: Para prevenir a lesão pulmonar em prematuros extremos, é necessário minimizar os vários fatores que desencadeiam a displasia broncopulmonar e utilizar estratégias terapêuticas menos agressivas. O melhor conhecimento desses fatores de risco da displasia broncopulmonar poderá gerar novas terapêuticas, que, conjuntamente com o tratamento utilizado atualmente para minimizar a lesão pulmonar, serão fundamentais para uma melhor evolução clínica desses prematuros extremos.

Effects of a nebulized NONOate, DPTA/NO, on group B streptococcus-induced pulmonary hypertension in newborn piglets.

NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus (GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4-10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 x 10(8) CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p <0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p <0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates.

Protective effect of pentoxifylline on volume-induced lung injury in newborn piglets.

To evaluate the efficacy of pentoxifylline (PTXF) in the attenuation of lung inflammation during volume-induced lung injury (VILI) in newborn piglets, 17 newborn piglets were mechanically ventilated with a large tidal volume (50 ml/kg) for a period of 8 h. They were randomly assigned to a placebo (PL, n = 9) or a treatment group (PTXF, n = 8) that received PTXF (20 mg/kg as a bolus, followed by a continuous infusion of 5 mg/kg/h). Hemodynamics, lung mechanics and arterial blood gases were measured during the 8 h of study. Serum and tracheoalveolar fluid (TAF) platelet-activating factor (PAF) and thromboxane (TXB(2)) levels were obtained at baseline and at 8 h, while lung tissue myeloperoxidase (MPO) and wet to dry weight were assessed after the completion of the study. In the PL group, a marked increase in TAF PAF and TXB(2) levels was observed only in TAF, suggesting that the inflammatory process was localized within the lungs. A significant decrease in lung tissue MPO activity (p < 0.005) and lung wet to dry weight ratio (p < 0.04) was observed in the PTXF group. There were no differences in hemodynamics, arterial blood gases or lung mechanics measurements between groups. A significant reduction in pulmonary inflammatory response was observed during VILI in the PTXF pretreated animals. These results suggest that PTXF may be effective in modulating lung inflammation associated with mechanical ventilation in neonates.