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Persistent Elastase/Proteinase Inhibitor Imbalance During 003 1-3998/89/2604-035 1$02.00/0 PEDIATRIC RESEARCH Vol. 26, No. 4, 1989 Copyright O 1989 International Pediatric Research Foundation, Inc. Printed in U.S.A. Persistent Elastase/Proteinase Inhibitor Imbalance during Prolonged Ventilation of Infants with Bronchopulmonary Dysplasia: Evidence for the Role of Nosocomial Infections H. WALTI, C. TORDET, L. GERBAUT, P. SAUGIER, G. MORIETTE, AND J. P. RELIER Neonatal Intensive Care Unit, Port-Royal Maternity, Paris [H. W., G.M., J.P.R., P.S.]; CNRS, Cellular Biology Center, Ivry [C. T.]; and Department of Biochemistry, Hopital St Vincent-de-Paul, Paris [L.G.] France ABSTRACT. Acute imbalance between elastase and a-1- Premature infants with acute neonatal lung injury, usually proteinase inhibitor (a1Pi) may contribute to the develop- RDS, may develop neonatal chronic pulmonary disease, of which ment of bronchopulmonary dysplasia (BPD). The question the most common form is BPD. The exact pathogenesis of BPD of whether such an imbalance persists in BPD infants still is unresolved, however, many recent reports emphasize the im- requiring mechanical ventilation after 4 wk of life has not portance of inflammatory events (1, 2). Histologic and cytologic been previously addressed. We studied 14 infants still on studies of infants with RDS have shown an early and significant mechanical ventilation at 4 wk of age: nine had BPD and alveolitis which consists of inflammatory cells (PMN and AM) five did not. Weekly (4 to 9 wk) serum and bronchoalveolar (1-4). This alveolitis is prolonged in infants with RDS who lavage (BAL) specimens were taken. alPi and a-2-mac- develop BPD (3). Activation of these cells within the lung (5, 6) roglobulin were measured in serum and BAL by immuno- leads to secretion and release of many products that alter function turbidimetric assay. BAL elastase activity was measured or damage lung cells and connective tissues. The potential role by cleavage of a synthetic substrate and expressed as ng in the pathogenesis of BPD of one of these products, the main of porcine pancreatic elastase equivalent. Infants with BPD proteolytic enzyme elastase, has recently been demonstrated in had higher levels of serum alPi and a-2-macroglobulin infants with RDS between the 2nd and the 28th d of postnatal than those without BPD. In contrast, the corresponding age. Two studies reported an elevation of BAL elastase levels, BAL levels were either similar or even decreased (a1Pi). coupled with low BAL levels of the main proteinase inhibitor Moreover, there was a 3-fold increase in elastase-1Pi a 1Pi. This results in an imbalance between elastase and a 1Pi (1, imbalance expressed as the BAL ng of porcine pancreatic 2). Moreover, this elastase-proteinase inhibitor imbalance has elastase equivalent/2alPi ratio. The role of nosocomial been associated with the destruction of lung connective tissue infections was evident in a subgroup of 11 infected BAL and the resultant fibrotic changes characteristic of BPD (7). The aspirates in BPD infants. In such cases we found a 3-fold question of whether such a BAL imbalance persists in BPD increase in the BAL ng of porcine pancreatic elastase infants still requiring MV after 28 d of life has not been addressed. equivalent/alPi ratio as compared to 35 noninfected BAL Furthermore, prolonged BPD is often associated with nosocomial in BPD infants. These data suggest a persistent alveolitis lung infections, and the role of such infections in elastolytic with imbalance between elastase and proteinase inhibitors damage has been recently emphasized in both acute and chronic in prolonged severe BPD. Such an imbalance is, in part, lung disease (8, 9). We designed a prospective study to answer explained by a local destruction and/or inactivation of alPi. the following questions: I) Is severe BPD that still requires Our results also emphasize the increase in proteolysis with mechanical ventilation at d 28 associated with elastase-proteinase nosocomial pneumonia. (Pediatr Res 26: 351-355, 1989) inhibitor imbalance? 2) Does MV per se result in such an imbalance? 3) Do nosocomial infections play a role in that Abbreviations imbalance? alPi, a-1-proteinase inhibitor a2M, a-2-macroglobulin MATERIALS AND METHODS AM, alveolar macrophage Patient groups. Fourteen low birth wt infants with or without BAL, bronchoalveolar lavage BPD, who still required MV at 28 d of age, were enrolled in the BPD, bronchopulmonary dysplasia study. The BPD group consisted of nine infants who fulfilled all MV, mechanical ventilation the following criteria: 1) Primary respiratory disorder requiring NPE, ng of porcine pancreatic elastase equivalent MV with supplemental oxygen from birth and for at least 3 d PMN, Polymorphonuclear (five infants had RDS, two pneumonia, and two severe wet lung PMSF, phenylmethylsulfonyl fluoride disease); 2) chronic respiratory distress at 28 d of age, requiring RDS, respiratory distress syndrome MV and supplemental oxygen to maintain Paol > 60 torr and SAPNA, N-succinyl-~(alanyl 3)-P-nitroanilide Paco2 < 45 tom; 3) chest x-ray 28 d postnatally consistent with methyl-pyrrolidine the diagnosis of BPD stage 111 or IV according to Northway et al. (10)r~iveinfants without BPD but with vro6nged MV served Received January 4, 1989; accepted April 2 1, 1989. as a'cohtrol group. These infants fulfilled alfthe folibwing criteria: Correspondence and reprint requests H. Walti, M.D., Service de Mtdecine 1) primary respiratory disorder, but MV birth Ntonatale, Hbpital Port Royal, 123 bd de Port Royal, 75674, Paris, France. N~ from for at H.W. was supported by a grant from la Fondation pour la recherche mCdicale, least 3 d without supplemental oxygen (the five infants enrolled Paris, France. had MV because of their low birth wt); 2) absence of significant ET AL. chronic respiratory distress, as described above, but necessity for we used their ratio expressed as NPE/2 pg alPi as previously MV (e.g. for apneas) at 28 d of age; 3) normal chest x-ray at 28 suggested by Ogden et al. (2). d of age. Chemical reagents. Porcine pancreatic elastase and SAPNA Study design. After informed consent was obtained from the were obtained from Biosys, Compikgne, France; PMSF and BSA parents, the 14 patients were studied weekly, from the 4th to the from Sigma Chemical Co., St. Louis, MO; EDTA and buffers 9th wk of life or until extubation. We performed I) BAL; 2) from Merck, Darmstadt, FRG; antibodies and standard proteins blood sampling; 3) recording of clinical data; 4) diagnosis of from Orimbio, Paris, France. nosocomial pneumonia. To reduce the potential influence of Data analysis. The data are given as mean k SD when distrib- adult blood transfusion on the results, no measurements were uted normally, otherwise as median and range. In our five control performed for a period of 48 h after transfusion. infants, values at increasing postnatal ages were not statistically Bronchoalveolar lavage. Tracheal emuents were obtained using different. We therefore combined the 14 corresponding values. a standardized technique of BAL (1, 2), by the same physioth- Differences between groups were evaluated with analysis of var- erapist as follows: 1 mL of sterile 0.9% NaCl was gently instilled iance if the data were normally distributed, or with nonparamet- into the endotracheal tube. Then the infant was ventilated for a ric tests: Mann-Whitney for unpaired values and Wilcoxon few breaths and deep endotracheal aspiration performed using a signed rank for paired values, if they were not. p < 0.05 was no. 6 French catheter. To rinse the side wall of the catheter, 1 taken as significant. mL of sterile 0.9% NaCl was then aspirated. The product of four lavages at 30-min intervals was collected in a sterile mucus RESULTS extractor. A total of 4 mL of sterile 0.9% NaCl was instilled. Mean amount of tracheal eMuent was not different between Patient data. The two groups, BPD (n = 9) and control (n = groups (3.35 f: 0.09 mL for controls and 3.42 f: 0.05 mL for 5), had similar birth wt and gestational ages. However, clinical BPD). Each BAL was refrigerated at 4°C before processing and evolution, as shown by requirements at d 1, and wk 4 and 8, of centrifuged at 1500 x g for 15 min at 4°C as soon as possible. oxygen, Fio2, and MV, expressed as a VI, were different (Table The cell free supernatant was frozen at -20°C until analysis. 1). Blood samples. One mL of blood was drawn by venous punc- Serum and BAL albumin. Serum albumin levels were not ture and plasma was separated by centrifugation and frozen significantly different between control and BPD infants at any within 2 h after sampling until analysis. sampling time. In contrast, weekly BAL albumin levels were Clinical data were recorded in order to assess requirement of increased in BPD infants. The difference was significant (p < oxygen (Fioz)and of MV, expressed as a ventilatory index (mean 0.05) only at wk 4 when the median (range) was 103 mg/L (33- airway pressure. Fioz/Pao2). 184) in BPD infants, in comparison to the overall median (range) Diagnosis of nosocomial pneumonia was made when all the 32 mg/L (1.4-67) in control infants. However, the latter value following criteria were present: 1) A dominant pathogenic mi- was not significantly different from the overall median (range) croorganism and altered PMN in routine tracheal aspirate cul- of 47 mg/L (9-462) for the BPD infants. tures; 2) clinical and radiologic signs of pneumonia; 3) laboratory Serum and BAL proteinase inhibitor. Table 2 shows that markers of infection (abnormal values for white blood count, C- weekly serum levels of the two proteinase inhibitors alPi and reactive protein, and fibrinogen).
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