Inflammatory Response to Oxygen and Endotoxin in Newborn Rat Lung Ventilated With Low Tidal Volume

Abstract

Herein, we determined the contribution of mechanical ventilation, hyperoxia and inflammation, individually or combined, to the cytokine/chemokine response of the neonatal lung. Eight-dayold rats were ventilated for 8 h with low (ϳ3.5 mL/kg), moderate (ϳ12.5 mL/kg), or high (ϳ25 mL/kg) tidal volumes (V T ) and the cytokine/chemokine response was measured. Next, we tested whether low-V T ventilation with 50% oxygen or a preexisting inflammation induced by lipopolysaccharide (LPS) would modify this response. High-, moderate-, and low-V T ventilation significantly elevated CXCL-2 and IL-6 mRNA levels. Low-V T ventilation with 50% oxygen significantly increased IL-6 and CXCL-2 expression versus low-V T ventilation alone. LPS pretreatment combined with low-V T ventilation with 50% oxygen amplified IL-6 mRNA expression when compared with low V T alone or low V T ϩ 50% O 2 treatment. In contrast, low V T up-regulated CXCL-2 levels were reduced to nonventilated levels when LPS-treated newborn rats were ventilated with 50% oxygen. Thus, low-V T ventilation triggers the expression of acute phase cytokines and CXC chemokines in newborn rat lung, which is amplified by oxygen but not by a preexisting inflammation. Depending on the individual cytokine or chemokine, the combination of both oxygen and inflammation intensifies or abrogates the low V T -induced inflammatory response. (Pediatr Res 68: 63-69, 2010) B ronchopulmonary dysplasia (BPD) remains the most important cause of respiratory morbidity in very low birth weight infants. Mechanical ventilation (MV), intra-uterine infections and oxidative stress up-regulate proinflammatory cytokines/chemokines including IL-1␤, IL-6, and IL-8 (1). Elevated concentrations of these cytokines/chemokines in amniotic fluid and bronchoalveolar lavage fluid (BALF) have been associated with BPD (2,3). The contribution of each risk factor, alone or combined, to the inflammatory response remains to be determined.Ample animal studies have suggested that high frequency oscillatory ventilation (HFOV) is less injurious compared with conventional ventilation (CMV) (4,5). However, in the baboon model of BPD impaired alveolarization and capillary development occurred in spite of appropriate oxygenation and use of HFOV (4). MV with moderate and high tidal volumes increased lung cytokine/chemokine response to systemic endotoxin in rabbits (6) and newborn rats (7). Oxidant injury alone can produce the pathologic features of BPD (8). Inflammatory cells such as monocytes and neutrophils are primary contributors to the oxygen-induced lung injury (9,10). Other animal studies have investigated the contributions of oxygen exposure and MV alone or in combination. In term ventilated piglets hyperoxia caused less lung damage than hyperoxia combined with hyperventilation but more than hyperventilation alone (11). Premature baboons ventilated with the minimum necessary supplemental oxygen had significant less damage than those ventilated with 100% oxygen (12), but alveolarization and capillary developmen...

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

“…Indeed, 195 genes showed an altered mRNA expression after LPS, compared to 17 and 11 after additional ventilation and oxygen treatment, respectively. This occurred despite the reduction of the amount of LPS of 33% compared to the dose used in three previous similar studies (4,7,9). This strong effect of LPS is even more astonishing, as these three studies showed that 24 h after the LPS injection (i.e., at the beginning of MV), the proinflammatory cytokine production was almost back to normal and the morphological aspect of the lung was comparable to the CTRL animals.…”

“…Thanks to an atraumatic intubation procedure performed under direct laryngoscopy, we were able to wean ventilated newborn rats off anesthesia and MV which allowed us then to perform outcome measurements after a chosen time period of recovery (7). In addition to the transitory increase of proinflammatory cytokines/chemokines measured in different studies immediately after MV and/or hyperoxia exposure in immature lungs (4,8,9), our previous study demonstrated changes in MMP9 and tropoelastin mRNA expression only as a delayed reaction 48 h after the ventilation episode (7). This indicated a second wave of gene regulation that could correspond to mechanisms occurring in premature infants developing BPD.…”

“…Models trying to decipher genes involved in the pathophysiology of BPD are mainly based on MV and oxygen application to young mammals with immature lungs of different species (3). In newborn rodent models, analyses of lung structure and gene and protein expression are performed for practical reasons directly at the end of MV (4)(5)(6). However, later appearing changes of gene expression might also have an impact on lung development and the evolution towards BPD and cannot be discovered by such models.…”

Standardization of pulmonary ventilation technique using volume-controlled ventilators in rats with congenital diaphragmatic hernia

“…Moreover, in all of them changes in lung molecular biology were noted after a short period of ventilation. In ventilation model of normal newborn rats, using simpler, volume-controlled, time-cycled ventilators, it may 24 or may not 18,25 be pressure-limited. The tidal volume admitted for ventilation ranged from 3.5 to 40 ml/kg, with a volume considered median between 8.5 and 12 ml/kg, and a frequency between 20 and 600 cycles/minute, with the median frequency between 100 and 160 cycles/minute.…”

Alterations in expression of elastogenic and angiogenic genes by different conditions of mechanical ventilation in newborn rat lung

“…BPD is a consequence of an inflammatory lung injury that leads to remodeling of the developing lung. Inflammation results from a variety of stimuli with mechanical ventilation, hyperoxia, and infection being the most prominent (22,48). The incidence of BPD increases with decreasing gestational age.…”