Abstract
Although progression to pulmonary fibrosis in preterm infants with respiratory distress syndrome (RDS) is related to the inflammatory response, the nature of this response remains controversial. We have therefore performed sequential bronchoalveolar lavages in 30 infants with RDS (13 of whom developed bronchopulmonary dysplasia) and 7 ventilated control infants, characterizing the cells obtained by immunohistochemical analysis of lineage-specific markers and assaying macrophage-associated chemokines and cytokines in supernatant fluid. At all ages from birth, lavage supernatants demonstrated highly significant increase over controls of the β-chemokine macrophage inflammatory protein (MIP)-1α, although not of regulated upon activation, normal T cell expressed and secreted (RANTES), of the cytokines tumor necrosis factor (TNF)-α and IL-1β, and of elastase/α-1 antitrypsin. Significantly higher concentrations of MIP-1α in particular were associated with the later development of fibrosis. Increased numbers of macrophages expressing the activation marker RM/3-1 were found at all ages in bronchopulmonary dysplasic infants, whereas neutrophil numbers were increased from d 3. Dexamethasone administered to 10 infants induced rapid decrease in inflammatory cell numbers and concentrations of MIP-1α, tumor necrosis factor-α, IL-1β, and elastase/α-1 antitrypsin. The inflammatory response in neonatal RDS begins within the first day of life. Long-term outcome is associated with the magnitude of this early response, in particular production of MIP-1α. The early introduction of specific therapy is thus likely to be beneficial.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- MIP-1α:
-
macrophage inflammatory protein-1α
- TNF-α:
-
tumor necrosis factor-α
- BAL:
-
bronchoalveolar lavage
- RANTES:
-
regulated upon activation, normal T cell expressed and secreted
- BPD:
-
bronchopulmonary dysplasia
References
Northway WH 1990 Bronchopulmonary dysplasia: then and now. Arch Dis Child 65: 1076–1081
Merritt TA, Cochrane CG, Holcomb K, Bohl B, Hallman M, Strayer P, Edwards DK 1983 Elastase and α1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome. J Clin Invest 72: 656–666
Murch SH, MacDonald TT, Wood CBS, Costeloe KL 1992 Tumour necrosis factor in the bronchoalveolar secretions of infants with the respiratory distress syndrome and the effect of dexamethasone treatment. Thorax 47: 44–47
Groneck P, Reuss D, Gotze-Speer B, Speer CP 1993 Effects of dexamethasone on chemotactic activity and inflammatory mediators in tracheobronchial aspirates of preterm infants at risk for chronic lung disease. J Pediatr 122: 938–944
Kovacs EJ 1991 Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol Today 12: 17–23
Kovacs EJ, DiPietro LA 1994 Fibrogenic cytokines and connective tissue production. FASEB J 8: 854–861
McGowan SE 1992 Extracellular matrix and the regulation of lung development and repair. FASEB J 6: 2895–2904
Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P 1989 Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med 170: 655–663
Piguet PF, Vesin C, Grau GE, Thompson RC 1993 Interleukin-1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica. Cytokine 5: 57–61
Arnon S, Grigg J, Silverman M 1993 Pulmonary inflammatory cells in ventilated preterm infants: effects of surfactant treatment. Arch Dis Child 69: 44–48
Unemori EN, Amento EP, Bauer EA, Horuk R 1993 Melanoma growth-stimulatory activity/GRO decreases collagen expression by human fibroblasts. Regulation by C-X-C but not C-C cytokines. J Biol Chem 268: 1338–1342
Gao J-L, Kuhns DB, Tiffany HL, McDermott D, Li X, Francke U, Murphy PM 1993 Structure and functional expression of the human macrophage inflammatory protein 1α/RANTES receptor. J Exp Med 177: 1421–1427
McColm JR, McIntosh N 1994 Interleukin-8 in bronchoalveolar secretions as predictor of chronic lung disease in premature infants. [letter; comment] Lancet 343: 729
Standiford TJ, Rolfe MW, Kunkel SL, Lynch JP, Burdick MD, Gilbert AR, Orringer MB, Whyte RI, Strieter RM 1993 Macrophage inflammatory protein-1α expression in interstitial lung disease. J Immunol 151: 2852–2863
Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT 1993 Localisation of tumour necrosis factor α by immunohistochemistry in chronic inflammatory bowel disease. Gut 34: 1705–1709
Finn A, Naik S, Klein N, Levinsky RJ, Strobel S, Elliott M 1993 Interleukin-8 release and neutrophil degranulation after pediatric cardiopulmonary bypass. J Thorac Cardiovasc Surg 106: 566–567
Watts CL, Bruce MC 1992 Effect of dexamethasone therapy on fibronectin and albumin levels in lung secretions of infants with bronchopulmonary dysplasia. J Pediatr 121: 597–607
Speer CP, Ruess D, Harms K, Herting E, Cefeller O 1993 Neutrophil elastase and acute pulmonary damage in neonates with severe respiratory distress syndrome. Pediatrics 91: 794–799
Bessler H, Sirota L, Notti I, Milo T, Djaldetti M 1993 IL-2 receptor gene expression and IL-2 production by human preterm newborns' cells. Clin Exp Immunol 93: 479–483
Klech H, Pohl W, for the European Society of Pneumonology Task Group on BAL 1989 Technical recommendations and guidelines for bronchoalveolar lavage (BAL). Eur Respir J 2: 561–585
Walters EH, Gardner PV 1991 Bronchoalveolar lavage as a research tool. Thorax 46: 613–618
Murch SH, Winyard PJD, Koletzko S, Wehner B, Cheema HA, Risdon RA, Phillips AD, Meadows N, Klein NJ, Walker-Smith JA 1996 Congenital enterocyte heparan sulphate deficiency is associated with massive albumin loss, secretory diarrhoea and malnutrition. Lancet 347: 1299–1301
Murch SH 1995 Sulphation of proteoglycans and intestinal function. J Gastroenterol Hepatol 10: 210–212
Murch SH, MacDonald TT, Walker-Smith JA, Levin M, Lionetti P, Klein NJ 1993 Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet 341: 711–714
Brandtzaeg P, Halstensen TS, Huitfeldt HS, Krajci P, Kvale D, Scott H, Thrane PS 1992 Epithelial expression of HLA, secretory component (poly-Ig receptor) and adhesion molecules in the human alimentary tract. Ann NY Acad Sci 664: 157–179
Sullivan DA, Vaerman JP, Soo C 1993 Influence of severe protein malnutrition on rat lacrimal, salivary and gastrointestinal immune expression during development, adulthood and ageing. Immunology 78: 308–317
Watts CL, Bruce MC 1995 Comparison of secretory component for immunoglobulin A with albumin as reference proteins in tracheal aspirates from preterm infants. J Pediatr 127: 113–122
Shanley TP, Schmal H, Friedl HP, Jones ML, Ward PA 1995 Role of macrophage inflammatory protein-1α (MIP-1α) in acute lung injury in rats. J Immunol 154: 4793–4802
Burdick MD, Kunkel SL, Lincoln PM, Wilke CA, Strieter RM 1993 Specific ELISAs for the detection of human macrophage inflammatory protein-1 α and β. Immunol Invest 22: 441–449
Christman JW, Blackwell TR, Cowan HB, Shepherd VL, Rinaldo JE 1992 Endotoxin induces the expression of macrophage inflammatory protein 1 alpha mRNA by rat alveolar and bone marrow-derived macrophages. Am J Respir Cell Mol Biol 7: 455–461
Brieland JK, Jones ML, Clarke SJ, Baker JB, Warren JS, Fantone JC 1992 Effect of acute inflammatory lung injury on the expression of monocyte inflammatory protein-1 (MCP-1) in rat pulmonary alveolar macrophages. Am J Respir Cell Mol Biol 7: 134–139
Lang RA, Cuthbertson RA, Dunn AR 1992 TNF-α, IL-1α and b-FGF are implicated in the complex disease of GM-CSF transgenic mice. Growth Factors 6: 131–138
Eichacker PQ, Hoffman WD, Farese A 1991 TNF but not IL-1 in dogs causes lethal lung injury and multiple organ dysfunction similar to human sepsis. J Appl Physiol 71: 1979–1989
Miyazaki Y, Araki K, Vesin C, Garcia I, Kapanci Y, Whitsett JA, Piguet P-F, Vassali P 1995 Expression of a tumor necrosis factor-α transgene in murine lung causes lymphocytic and fibrosing alveolitis. J Clin Invest 96: 250–259
Leff JA, Baer JW, Bodman ME, Kirkman JM, Shanley PF, Patton LM, Beehler CJ, McCord JM, Repine JE 1994 Interleukin-1-induced lung neutrophil accumulation and oxygen metabolite-mediated lung leak in rats. Am J Physiol 266:L2–L8
Murch SH, Costeloe K, Klein NJ, Rees H, McIntosh N, Keeling JW, MacDonald TT Mucosal Tumor necrosis factor-α production and extensive disruption of sulfated glycosaminoglycans begin within hours of birth in neonatal respiratory distress syndrome. Pediatr Res 1996; 40: 484–489
Durand M, Sardesai S, McEvoy C 1995 Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomised controlled trial. Pediatrics 95: 584–590
Windsor AC, Walsh CJ, Mullen PG, Cook DJ, Fisher BJ, Blocher CR, Leeper-Woodford SK, Sugerman HJ, Fowler AA III 1993 Tumor necrosis factor-α blockade prevents neutrophil CD18 receptor upregulation and attenuates lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation. J Clin Invest 91: 1459–1468
Author information
Authors and Affiliations
Additional information
Funded by Action Research. S.H.M. was supported by Action Research and T.T.M. by the Wellcome Trust. The University Department of Paediatric Gastroenterology has now moved to the Royal Free Hospital, London (S.H.M.).
Rights and permissions
About this article
Cite this article
Murch, S., Costeloe, K., Klein, N. et al. Early Production of Macrophage Inflammatory Protein-1α Occurs in Respiratory Distress Syndrome and Is Associated with Poor Outcome. Pediatr Res 40, 490–497 (1996). https://doi.org/10.1203/00006450-199609000-00020
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199609000-00020
This article is cited by
-
CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest
Cell Death & Disease (2021)
-
Interleukin-4 and 13 concentrations in infants at risk to develop Bronchopulmonary Dysplasia
BMC Pediatrics (2003)
-
Lung Pathology in Premature Infants withUreaplasma urealyticumInfection
Pediatric and Developmental Pathology (2002)
