Lung and Systemic Inflammation in Preterm Lambs on Continuous Positive Airway Pressure or Conventional Ventilation

Abstract

Intratracheal lipopolysaccharide (LPS) causes acute inflammation and injurious mechanical ventilation results in pulmonary and systemic inflammation. We aimed to determine in preterm lungs if continuous positive airway pressure (CPAP) protects against pulmonary and systemic inflammation, compared with conventional mechanical ventilation (CMV) after intratracheal LPS. Preterm fetuses were exposed to maternal betamethasone and Epostane 36 h before delivery at 133 d gestational age (term ϭ 150 d). Lambs were intubated and randomized to receive gentle CMV (tidal volume 8 mL/kg) or CPAP with 8 cm H 2 O pressure. Surfactant (10 mg/kg) mixed with 1 mg LPS or saline was instilled into the trachea at 15 min. Blood gas status, ventilation variables, and arterial pressures were recorded for 3 h. Static pressure-volume curves and lung and systemic inflammation were assessed postmortem. CPAP lambs had elevated Paco 2 and minute ventilation compared with the CMV lambs. Cytokine mRNA was increased in the lungs and liver of CPAP and CMV lambs relative to unventilated controls. Intratracheal LPS amplified the cytokine mRNA responses of IL-1␤, IL-6, and IL-8 in the lung and liver. Blood neutrophils decreased similarly after LPS in CPAP and CMV groups. Cytokine markers of lung injury or the systemic response to intratracheal LPS were not decreased by CPAP relative to CMV, in preterm lambs. . Similarly, ventilation with lung volumes that approach or exceed total lung capacity will stretch the lungs and cause injury (3,4). The preterm fetal lung is particularly vulnerable to lung injury during the transition from a fluid-filled lung to airway breathing because surfactant deficiency increases the pressures required to open the lung, the lung aerates nonuniformly, and the delicate tissues of the preterm lung are easily stretched (5,6). The use of continuous positive airway pressure (CPAP) is being advocated for transitioning the preterm fetal lung to air breathing as a way to decrease lung injury (7,8). Although CPAP can cause lung injury in sepsis models (9), CPAP can decrease indicators of lung injury in preterm lambs (10) compared with conventional mechanical ventilation (CMV) and its use has been associated with decreased bronchopulmonary dysplasia (11).Prior exposure of the adult lung to pro-inflammatory mediators such as endotoxin amplifies lung injury caused by ventilation from low lung volumes or elevated lung volumes (9,12,13), and the mediators can enter the systemic circulation and cause systemic inflammatory responses (14,15). Termventilated lambs do not leak endotoxin from the airspaces into the systemic circulation unless the lungs are over-stretched (16). In contrast, preterm lungs leak endotoxin or IL-1 with conventional ventilation (16,17). Chorioamnionitis is associated with many preterm deliveries before 32 wk gestational age, and inflammatory mediators are present in the fetal lung (18,19). We hypothesized that spontaneous breathing with CPAP would protect the preterm lung and minimize a systemic inflamma...

Variable ventilation enhances ventilation without exacerbating injury in preterm lambs with respiratory distress syndrome

“…As compared with unventilated fetal controls, the ventilated groups had increased mRNA expression of early response markers of lung injury (CTGF, CYR61, and EGR1) (16) as well as IL-1β and IL-6, noted previously as indicators of volutrauma in our preterm lamb model (17)(18)(19). Similarly, BAL inflammatory cells, EGR1, and MPO protein expression in the tissue were increased in CV and VV animals as compared with fetal controls, although lung tissue injury scores did not differ.…”

Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs

“…All lambs received prophylactic surfactant (100 mg/kg, Curosurf; Chiesi Farmaceutici) at 15 min. Lambs were subsequently ventilated in volume guarantee mode with a VT of 7 ml/kg, which is the normal VT for lambs at this gestation (44). Throughout ventilation, lambs were sedated by continuous infusion of Alfaxane (3 mg·kg Ϫ1 ·min Ϫ1 ) through an umbilical vein catheter implanted immediately after delivery.…”

“…The initiation of mechanical ventilation of the preterm lung, irrespective of how it is conducted, produces lung inflammation and injury (10,44,60). The key proinflammatory cytokines initiated by ventilation are IL-1␤, IL-6, and IL-8.…”

“…The initiation of mechanical ventilation elicits a profound inflammatory response within the immature lung (21,27,44) and may, in turn, induce ventilation-induced lung injury (VILI), which causes airway remodeling and potential long-term pulmonary consequences (10,60). Increased lung inflammation and injury following mechanical ventilation has been demonstrated in preterm experimental models (3,14,44) and preterm infants (63). An increased requirement for ventilator support, such as higher tidal volumes (VT) and/or pressures, increases lung inflammation and injury (61).…”

Ventilation-Mediated Injury After Preterm Delivery of Ureaplasma parvum Colonized Fetal Lambs

“…However, the effects of mechanical ventilation associated with the initiation of ventilation on fetal lungs with chronic ureaplasma infection are unknown. Our previous studies with acute exposures to lipopolysaccharide (LPS) showed an amplification of inflammation with ventilation (18). However, chronic fetal proinflammatory exposures may result in a tolerance phenomenon with suppressed inflammation (19).…”