Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury.

Animal models of acute lung injury.

Intermittent positive pressure ventilation with large tidal volumes and high peak airway pressures can result in pulmonary barotrauma. In the present study, we examined the hypothesis that ventilation at very low lung volumes can also worsen lung injury by repeated opening and closing of airway and alveolar duct units as ventilation occurs from below to above the infection point (Pinf) as determined from the inspiratory pressure-volume curve. We ventilated isolated, nonperfused, lavaged rat lungs with physiologic tidal volumes (5 to 6 ml/kg) at different end-expiratory pressures (above and below Pinf) and studied the effect on compliance and lung injury. In the groups ventilated with positive end-expiratory pressure (PEEP) below Pinf compliance fell dramatically after ventilation. It did not change in either the control group or the group ventilated with PEEP above Pinf. Lung injury assessed morphologically was significantly greater in the groups ventilated with a PEEP below Pinf, and in these groups the ...

Tidal ventilation at low airway pressures can augment lung injury.

ARDS includes a complex series of events leading to alveolar damage, high permeability pulmonary edema, and respiratory failure. The endogenous pulmonary surfactant system is crucial to maintaining normal lung function, and only recently has it been appreciated that alterations in the surfactant system significantly contributed to the pathophysiology of the lung injury of patients with ARDS. Through a combination of analyzing BAL samples from patients with ARDS and extensive animal studies, there have been significant insights into the variety of surfactant abnormalities that can occur in injured lungs. These include altered surfactant composition and pool sizes, abnormal surfactant metabolism, and inactivation of alveolar surfactant by serum proteins present within the airspace. Positive effects of exogenous surfactant administration on acute lung injury have been reported. There is now a prospective, randomized clinical trial evaluating the efficacy of aerosolized exogenous surfactant in patients with ARDS. This trial has demonstrated improvements in gas exchange and a trend toward decreased mortality in response to the surfactant. Despite these encouraging results, there are multiple factors requiring further investigation in the development of optimal surfactant treatment strategies for patients with ARDS. Such factors include the development of optimal surfactant delivery techniques, determining the ideal time for surfactant administration during the course of injury, and the development of optimal exogenous surfactant preparations that will be used to treat these patients. With further clinical trials and continued research efforts, exogenous surfactant administration should play a useful role in the future therapeutic approach to patients with ARDS.

Surfactant and the Adult Respiratory Distress Syndrome

Rationale: In normal lungs, local changes in pleural pressure (Ppl) are generalized over the whole pleural surface. However, in a patient with injured lungs, we observed (using electrical impedance tomography) a pendelluft phenomenon (movement of air within the lung from nondependent to dependent regions without change in tidal volume) that was caused by spontaneous breathing during mechanical ventilation.Objectives: To test the hypotheses that in injured lungs negative Ppl generated by diaphragm contraction has localized effects (in dependent regions) that are not uniformly transmitted, and that such localized changes in Ppl cause pendelluft.Methods: We used electrical impedance tomography and dynamic computed tomography (CT) to analyze regional inflation in anesthetized pigs with lung injury. Changes in local Ppl were measured in nondependent versus dependent regions using intrabronchial balloon catheters. The airway pressure needed to achieve comparable dependent lung inflation during paralysis versus ...

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Spontaneous effort causes occult pendelluft during mechanical ventilation.

Chez le lapin la ventilation a haute frequence ameliore les echanges gazeux. Les oscillations a haute frequence protegent le poumon des membranes hyalines contrairement a la ventilation traditionnelle

Comparison of conventional and high-frequency ventilation: oxygenation and lung pathology.

Using adult guinea-pigs, we have developed an experimental model in which alveolar surfactant phospholipids are removed by repeated lung lavage in vivo, and in which the short-term survival of the animals is ensured by artificial ventilation. Blood gases, parameters of lung mechanics, and histologic and electron microscopic findings indicate that the lavage procedure induces a condition similar to the adult respiratory distress syndrome. We propose that our technique might be used for evaluation of pharmacological agents and various forms of artificial ventilation which have been suggested for treatment of this disease.

In vivo lung lavage as an experimental model of the respiratory distress syndrome.

Objective:

To evaluate the effect of aerosolized modified natural surfactant in adult rats with respiratory failure.



Methods: Lung-lavaged adult rats were treated with aerosolized surfactant, aerosolized saline or a bolus of surfactant. Surfactant was labelled with dimyristoylphosphatidylcholine (DMPC) and human serum albumin was given intravenously for evaluation of lung protein leakage. Blood gases and dynamic compliance were measured intermittently. At the end of ventilation, the lungs were either fixed by vascular perfusion for histological examination or washed for determination of total phospholipids, DMPC and human albumin in the lavage fluid.



Results: Treatment with bolus surfactant led to a quick and sustained restoration of pre-lavage blood gas values in most animals. The response to aerosolized surfactant varied considerably, with an overall moderate improvement of gas exchange. The saline-treated group failed to show any significant recovery of lung function. No histopathological differences were found between any of the groups. On average 0.46% of total administered aerosolized surfactant could be recovered. Vascular-to-alveolar leakage of human albumin averaged 11%, with no significant differences between the groups. Final values for PaO2 were significantly correlated with total phospholipids in the lavage fluid, and inversely related to the vascular-to-alveolar leakage of albumin.



Conclusion: Neither bolus nor aerosolized surfactant influenced lung morphology. Nebulized surfactant improved lung function but the effect was inferior to that obtained with bolus surfactant, and the outcome depended on the balance between the combined pool size of exogenous and endogenous surfactant and the vascular-to-alveolar leakage of serum protein.

Aerosolized surfactant in lung-lavaged adult rats: factors influencing the therapeutic response.

23 guinea pigs were exposed to 15 mg/m3 HCl gas 5 days/week, 2 hours daily, for 7 weeks. 15 animals served as controls. From the 5th day of exposure, the following lung function parameters were evaluated in anaesthetised animals: VT, fR, minute volume, TGV, Vmax, R1, Rw, Rrs, Cl, Cw, Crs, delta Poes/VT, hemoglobin, SaO2, PaO2, PaCO2, pH, SBC, BE. These measurements showed no differences between HCl-exposed animals and controls. Histological examination of the lungs revealed no changes which could be attributed to HCl-exposure. This study relates to the important question whether lung damage can be induced by industrially produced, intermittent high levels of HCl in the environment.

B. Robertson

Papers

In vivo lung lavage as an experimental model of the respiratory distress syndrome.

Aerosolized surfactant in lung-lavaged adult rats: factors influencing the therapeutic response.

The effect of intermittent hydrogen chloride exposure on the lung function of the guinea pig