The effects of long-term conventional mechanical ventilation on the lungs of adult rats.

BACKGROUND: Ventilation-induced lung injury is often studied in animal models by using ventilation strategies with high-tidal volumes and high-oxygen concentration over a relatively short period of time. The injury induced by these ventilation strategies includes alterations to the surfactant system and up-regulation of inflammatory markers. Whether these responses to ventilation occur with more clinically relevant ventilation strategies is not known. OBJECTIVE: To assess how healthy adult rats respond to 24 hrs of conventional mechanical ventilation with respect to lung physiology, markers of inflammation, and alterations to pulmonary surfactant, and how this is affected by the oxygen concentration. INTERVENTIONS: Adult rats were mechanically ventilated for 24 hrs with a tidal volume of 8 mL/kg, 5 cm H2O positive end-expiratory pressure, at 60 breaths/min with either 21% or 100% oxygen. Animals were monitored for blood oxygenation and other physiologic parameters. After ventilation, lungs were lavaged and analyzed for inflammatory markers and pulmonary surfactant. These outcomes were compared with measurements obtained from spontaneously breathing rats exposed to either 21% or 100% oxygen for 24 hrs. MAIN RESULTS: Twenty-four hours of ventilation did not result in significant changes in blood oxygenation. Inflammatory markers, such as interleukin-6 concentration and the number of neutrophils in the lavage, were increased in ventilated animals compared with the nonventilated controls, regardless of the level of inspired oxygen. The amount of active surfactant was increased after ventilation; however, the surface activity of this material was impaired as compared with controls. CONCLUSION: Prolonged mechanical ventilation of health lungs with a physiologically benign strategy can contribute to the inflammatory response and cause alterations to pulmonary surfactant.

Lung mechanics in the TIMP3 null mouse and its response to mechanical ventilation.

Tissue inhibitor of metalloproteinase-3 (TIMP3) null mice develop emphysema-like airspace enlargement due to an enzymatic imbalance. This study investigates how these abnormalities alter lung mechanics and the response to 2 different mechanical ventilation strategies. Phenotypically, TIMP3 null mice had increased compliance, and decreased resistance, tissue damping, and tissue elastance over wild-type controls. Decreased compliance and increased resistance were observed following the injurious ventilation strategy; however, the TIMP3 null response to both ventilation strategies was similar to wild-type mice. In conclusion, TIMP3 null mice have significant alterations in lung mechanics; however, this does not affect their response to ventilation.

Physiological effects of oxidized exogenous surfactant in vivo: effects of high tidal volume and surfactant protein A.

Oxidative damage to surfactant can decrease lung function in vivo. In the current study, our two objectives were: 1) to examine whether the adverse effects of oxidized surfactant would be accentuated in animals exposed to high tidal volume ventilation, and 2) to test whether supplementation with surfactant protein A (SP-A) could improve the function of oxidized surfactant in vivo. The first objective was addressed by evaluating the response of surfactant-deficient rats administered normal or oxidized surfactant and then subjected to low tidal volume (6 ml/kg) or high tidal volume (12 ml/kg) mechanical ventilation. Under low tidal volume conditions, rats administered oxidized surfactant had impaired lung function, as determined by lung compliance and arterial blood gas analysis, compared with nonoxidized controls. Animals subjected to high tidal volume ventilation had impaired lung function compared with low tidal volume groups, regardless of the oxidative status of the surfactant. The second experiment demonstrated a significantly superior physiological response in surfactant-deficient rats receiving SP-A containing oxidized surfactant compared with oxidized surfactant. Lavage analysis at the end of the in vivo experimentation showed no differences in the recovery of oxidized surfactant compared with nonoxidized surfactant. We conclude that minimizing excessive lung stretch during mechanical ventilation is important in the context of exogenous surfactant supplementation and that SP-A has an important biophysical role in surfactant function in conditions of oxidative stress. Furthermore, the oxidative status of the surfactant does not appear to affect the alveolar metabolism of this material.

Physiological and inflammatory response to instillation of an oxidized surfactant in a rat model of surfactant deficiency.

Pulmonary surfactant is a mixture of phospholipids ( approximately 90%) and surfactant-associated proteins (SPs) ( approximately 10%) that stabilize the lung by reducing the surface tension. One proposed mechanism by which surfactant is altered during acute lung injury is via direct oxidative damage to surfactant. In vitro studies have revealed that the surface activity of oxidized surfactant was impaired and that this effect could be overcome by adding SP-A. On the basis of this information, we hypothesized that animals receiving oxidized surfactant preparations would exhibit an inferior physiological and inflammatory response and that the addition of SP-A to the oxidized preparations would ameliorate this response. To test this hypothesis, mechanically ventilated, surfactant-deficient rats were administered either bovine lipid extract surfactant (BLES) or in vitro oxidized BLES of three doses: 10 mg/kg, 50 mg/kg, or 10 mg/kg + SP-A. When instilled with 10 mg/kg normal surfactant, the rats had a significantly superior arterial Po2 responses compared with the rats receiving oxidized surfactant. Interestingly, increasing the dose five times mitigated this physiological effect, and the addition of SP-A to the surfactant preparation had little impact on improving oxygenation. There were no differences in alveolar surfactant pools and the indexes of pulmonary inflammation between the 10 mg/kg dose groups, nor was there any differences observed between either of the groups supplemented with SP-A. However, there was significantly more surfactant and more inflammatory cytokines in the 50 mg/kg oxidized BLES group compared with the 50 mg/kg BLES group. We conclude that instillation of an in vitro oxidized surfactant causes an inferior physiological response in a surfactant-deficient rat.

High oxygen concentrations predispose mouse lungs to the deleterious effects of high stretch ventilation.

Mechanical ventilation is a necessary intervention for patients with acute lung injury. However, mechanical ventilation can propagate acute lung injury and increase systemic inflammation. The exposure to >21% oxygen is often associated with mechanical ventilation yet has not been examined within the context of lung stretch. We hypothesized that mice exposed to >90% oxygen will be more susceptible to the deleterious effects of high stretch mechanical ventilation. C57B1/6 mice were randomized into 48-h exposure of 21 or >90% oxygen; mice were then killed, and isolated lungs were randomized into a nonstretch or an ex vivo, high-stretch mechanical ventilation group. Lungs were assessed for compliance and lavaged for surfactant analysis, and cytokine measurements or lungs were homogenized for surfactant-associated protein analysis. Mice exposed to >90% oxygen + stretch had significantly lower compliance, altered pulmonary surfactant, and increased inflammatory cytokines compared with all other groups. Our conclusion is that 48 h of >90% oxygen and high-stretch mechanical ventilation deleteriously affect lung function to a greater degree than stretch alone.