Optimal Positive End-Expiratory Pressure Fails to Preserve Nonrespiratory Lung Function in Acute Lung Injury

lung injury during conventional ventilation in the A cute premature lamb with respiratory distress syndrome (RDS) is characterized by progressive deterioration in gas exchange and lung inflammation. Inhaled nitric oxide (iNO), high-frequency oscillatory ventilation (HFOV), and partial liquid ventilation (PLV) have been proposed as new therapies that may improve oxygenation while minimizing the severity of acute lung injury. The relative and combined effectiveness of these three therapies in improving gas exchange and decreasing inflammation in severe RDS is uncertain. We hypothesized that the two lung recruitment strategies (HFOV and PLV) would have similar effects on gas exchange and lung inflammation, and would augment the response to low-dose iNO. To test this hypothesis, we studied the individual and combined effects of iNO, HFOV, and PLV in 31 extremely premature lambs (115 days, 0.78 term; 147 days 5 term) using seven mechanical ventilation protocols. Premature animals were delivered by cesarean section and treated with surfactant before beginning mechanical ventilation for 4 h with fraction of inspired oxygen 5 1.00. Four groups were treated with conventional ventilation (CV control, n 5 5; CV 1 iNO, n 5 5; CV 1 PLV, n 5 5; CV 1 PLV 1 iNO, n 5 4). Three groups were treated with HFOV (HFOV control, n 5 5; HFOV 1 iNO, n 5 4; HFOV 1 PLV, n 5 3). Arterial blood gases were recorded hourly. At the end of the study, the lungs were prepared for histology and assessments of lung neutrophil accumulation using a myeloperoxidase assay. We found that control CV animals had progressive deterioration in gas exchange over the 4-h study period (arterial-alveolar oxygen ratio [a/AO2] at 4 h 5 0.07 6 0.01). In contrast, both HFOV and CV 1 PLV improved oxygenation at 4 h (HFOV a/AO2 5 0.27 6 0.06; PLV a/AO2 5 0.25 6 0.04; p , 0.01 vs CV). Both lung recruitment strategies improved oxygenation when combined with iNO (5 ppm). PLV did not improve oxygenation when combined with HFOV, but allowed the use of lower airway pressures. Lung neutrophil accumulation (myeloperoxidase assay, units per gram of lung tissue) was markedly reduced by HFOV (0.06 6 0.06), CV 1 PLV (0.16 6 0.08), and CV 1 iNO (0.11 6 0.04) compared with CV (0.53 6 0.20, p , 0.05). We conclude that HFOV and PLV cause similar improvements in gas exchange and equivalent attenuation of lung neutrophil accumulation in extremely premature lambs with RDS. Both lung recruitment strategies augmented the oxygenation response to low-dose iNO. We speculate that these lung recruitment strategies could favorably modulate the inflammatory component of lung injury in clinical RDS, and that combined treatments may improve the respiratory outcome of premature neonates. *From the Pediatric Heart Lung Center, and the Departments of Pediatrics (Drs. Kinsella, Parker, and Abman), Obstetrics and Gynecology (Dr. Galan), and Surgery (Dr. Sheridan), University of Colorado School of Medicine, Denver, CO. Correspondence to: John P. Kinsella, MD, Pediatric Heart Lung Center, Department of Pediatrics, Children’s Hospital, 1056 East 19th Ave, Denver, CO 80218 16S

Optimal Positive EndExpiratory Pressure Fails to Preserve Nonrespiratory Lung Function in Acute Lung Injury* K. Creamer, MD; L. McCloud; L. Fisher, MD; and I. Ehrhart

(CHEST 1999; 116:16S–17S) ur objective was to test the hypothesis that optimal positive end-expiratory pressure (PEEP) would diminish the manifestations of lung injury.

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Materials and Methods Isolated dog lungs were perfused with blood and mechanically ventilated with a ventilator (model 900C; SiemensElema AB; Solna, Sweden). Ventilation was performed with PEEP (4.6 6 1 cm H2O) and tidal volume (10.7 6 9 mL/kg) determined individually for each lobe, to keep end-expiratory lung volume above closing volume and to avoid overdistention. Three groups were followed up with serial measures of lung injury, which included static compliance (Csta), WBC counts with differentials, and pulmonary vascular resistance. In addition, indexes of endothelial function were performed using first-pass metabolism of tritiated benzoyl-Phe-Ala-Pro ([3H]-BPAP), a substrate of angiotensin-converting enzyme. [3H]-BPAP was used to measure dynamically perfused surface area and percent metabolism by pulmonary vascular endothelium. After 1 h of stable perfusion and ventilation, baseline measurements were obtained. The injury and intervention groups were then injured with phorbol myristate acetate (0.1 mg/mL of perfusate), a potent neutrophil and platelet activator. Ten minutes after injury, the intervention group had the PEEP increased to optimal PEEP (mean 10 6 4 cm H2O), as determined by pressure-volume curves of previously injured lobes. Forty minutes after injury, follow-up measurements were taken. Results for each group were compared vs baseline and vs control with t tests and analysis of variance.

Results The control group remained in stable condition throughout the experiment. Although optimized PEEP allowed preservation of Csta in the intervention group, it failed to blunt other manifestations of lung injury (Table 1). All measures of nonrespiratory function worsened in both injury and intervention groups.

Conclusions Optimal PEEP preserves respiratory function as measured by Csta but does not blunt the effects of acute lung injury on the other functions of the lung. This study highlights the distinction between respiratory and nonrespiratory functions of the lung. *From the Medical College of Georgia, Vascular Biology Center, and Pediatric Critical Care, Augusta, GA. Correspondence to: Kevin Creamer, MD, Pediatric Critical Care, Children’s Medical Center, 1446 Harper St, Augusta, GA 30912 Thomas L. Petty 41st Annual Aspen Lung Conference: Acute Lung Injury

Table 1—Effects of PEEP in Acute Lung Injury Group Effects

Control

Injury

Intervention

N Compliance D WBC D Neutrophil number D PVR D† Amax/Km D† % Metabolism D

6 29% 216% 241% 16% 23% 0%

9 243%* 288%* 288%* 1204%* 219%* 29%*

8 213% 279%* 278%* 1225%* 220%* 28%*

*Indicates p , 0.02 vs control and baseline (preinjury) measures. †PVR 5 pulmonary vascular resistance; Amax/Km 5 dynamically perfused surface area.

Hyaluronan Fragments Induce Plasminogen Activator Inhibitor-1 and Inhibit Urokinase Activity in Mouse Alveolar Macrophages* A Potential Mechanism for Impaired Fibrinolytic Activity in Acute Lung Injury M. R. Horton, MD; M. A. Olman, MD; and P. W. Noble, MD

(CHEST 1999; 116:17S) mpaired fibrinolytic activity within the lung is an important component of acute lung injury. Recent evidence has suggested that the inability to resorb fibrin may contribute to increased lung fibrosis in animal models of acute lung injury. Overexpression of plasminogen activator inhibitor-1 (PAI-1) in transgenic mice resulted in increased lung collagen deposition following treatment with bleomycin.1 Macrophages are an important source of PAI-1 activity, but the mechanisms that regulate PAI-1 expression in alveolar macrophages are poorly understood. Turnover of the extracellular matrix has been shown to be an early event in acute lung injury. One component of the extracellular matrix that has been shown to be increased in animal models of acute lung injury and in patients with ARDS is the glycosaminoglycan hyaluronan (HA). Recent work from our laboratory has shown that lowermolecular-weight fragments of HA can induce the expression of a number of inflammatory mediators in macrophages.2,3 We hypothesized that HA fragments may induce PAI-1 activity and down-regulate fibrinolytic activity in mouse alveolar macrophages. To test this hypothesis, we stimulated

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*From the Divisions of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, University of Alabama, Birmingham, AL, and Yale University School of Medicine, New Haven, CT, and the VA-CT Healthcare System, West Haven, CT. Correspondence to: Paul Noble, MD, Yale University School of Medicine, LCI 105, 333 Cedar St, PO Box 208057, New Haven, CT 06520-8057

a mouse alveolar macrophage cell line (MH-S) with HA fragments over time, isolated messenger RNA, and examined PAI-1 and urokinase expression by Northern analysis. HA fragments induced PAI-1 messenger RNA with a maximal response between 3 to 6 h. HA also inhibited the baseline urokinase expression. Western blot analysis demonstrated up-regulation of PAI-1 protein following exposure of MH-S cells to HA fragments. Importantly, inhibition of fibrinolytic activity was demonstrated by zymography. Together, these data suggest that one mechanism for impaired fibrinolytic activity in acute lung injury may be through the effects of HA fragments on alveolar macrophage PAI-1 expression.

References 1 Eitzman DT, McCoy RD, Zheng X, et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996; 97:232–237 2 McKee CM, Penno MB, Cowman M, et al. Hyaluronan fragments induce chemokine gene expression in alveolar macrophages: the role of HA size and CD44. J Clin Invest 1996; 98:2403–2413 3 McKee CM, Lowenstein C, Horton MR, et al. Hyaluronan fragments induce nitric oxide synthase in murine macrophages through an NF-kB-dependent mechanism. J Biol Chem 1997; 272:8013– 8018

Gelatinase B Deficiency Does Not Protect Against Lipopolysaccharide-Induced Acute Lung Injury* Tomoko Betsuyaku, MD, PhD; J. Michael Shipley, PhD; Zhi Liu, PhD; and Robert M. Senior, MD

(CHEST 1999; 116:17S–18S) olymorphonuclear leukocytes (PMNs) contain gelatinase B, a matrix metalloproteinase that is readily released from these cells upon stimulation with a variety of agents. Because gelatinase B degrades basement membrane components, and because inhibition of matrix metalloproteinase activity blunts PMN migration through basement membrane in vitro, gelatinase B may be required for PMN emigration in the lung and other tissues. High levels of gelatinase B have been reported in BAL fluid in ARDS patients, raising the possibility that gelatinase B contributes to the pathophysiology of ARDS. To test whether gelatinase B is necessary for PMN emigration in the lung and to determine the role of gelatinase

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*From the Pulmonary and Critical Care Medicine Division, Washington University School of Medicine (Drs. Betsuyaku, Shipley, and Senior), St. Louis, MO, and the Department of Dermatology, Medical College of Wisconsin (Dr. Liu), Milwaukee, WI. Supported by the National Institutes of Health. Dr. Betsuyaku is a Fellow of the Japan Society for the Promotion of Science for Young Scientists. Dr. Shipley is a Parker B. Francis Fellow. Correspondence to Tomoko Betsuyaku, MD, Pulmonary and Critical Care Medicine, Barnes Jewish Hospital, 216 S Kingshighway Blvd, St. Louis, MO 63110 CHEST / 116 / 1 / JULY, 1999 SUPPLEMENT

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