Background: Oxidant-induced tissue damage is thought to contribute to the lung injury seen in patients with acute respiratory distress syndrome (ARDS). Ceruloplasmin (CP) is a major circulating antioxidant, increased levels of which have been measured in bronchoalveolar lavage fluid (BALF) taken from such patients. Traditionally, CP detected in these circumstances was thought to be plasma-derived, moving into the alveolar spaces as a consequence of the increased alveolar-capillary permeability that characterises ARDS. However, recent studies in murine models suggest that CP may be synthesised in the airways and even alveoli under physiological conditions. Objectives: The aims of this investigation were therefore to identify the source of any increased levels of CP detectable in BALF taken from patients with established ARDS. Methods: Matched BALF and plasma samples taken from patients with ARDS (n = 46) and from controls without lung disease (n = 11) were analysed for CP (132 kD) and plasma specific albumin (ALB, 68 kD) and (α2-macroglobulin (α2-M, 820 kD). Results: All three proteins were increased in BALF taken from patients with ARDS compared to controls (p < 0.01, ALB and CP; p < 0.001, α2-M). When protein levels were expressed as the ratios of BALF: plasma (designated Q), QCP and Qα2-M increased in parallel to QALB (p < 0.001), indicating that all increases were primarily plasma-derived. Their relative coefficients of excretion (RCE: QCP/QALB and Qα2-M/QALB) demonstrated that the larger molecular weight protein, α2-M, gave the best discrimination between patients with ARDS and normal controls (0.85 vs. 0.04; p < 0.01), indicating that this was the most sensitive marker of alveolar-capillary permeability. Conclusions: Increased levels of CP in BALF from patients with ARDS are mainly attributable to plasma exudation.

Keywords:
Ceruloplasmin, Acute respiratory distress syndrome, Bronchoalveolar lavage fluid
1.
Baldwin SR, Grum CM, Boxer LA, Simon RH, Ketai LH, Devall LJ: Oxidant activity in expired breath of patients with adult respiratory distress syndrome. Lancet 1986;i:11–14.
2.
Cochrane CG, Spragg R, Reval SD: Pathogenesis of the adult respiratory distress syndrome. Evidence of oxidant activity in bronchoalveolar lavage fluid. J Clin Invest 1983;71:754–761.
3.
Fisher AB: Oxygen therapy. Side effects and toxicity. Am Rev Respir Dis 1980;122:61–69.
4.
Broadley C, Hoover RL: Ceruloplasmin reduces the adhesion and scavenges superoxide during the interaction of activated polymorphonuclear leukocytes with endothelial cells. Am J Pathol 1989; 135:647–655.
5.
Krsek-Staples JA, Kew RR, Webster RO: Ceruloplasmin and transferrin levels are altered in serum and bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am Rev Respir Dis 1992;145:1009–1015.
6.
Yang F, Friedrichs WE, deGraffenried L, Herbert DC, Weaker FJ, Bowan BH, Coalson JJ: Cellular expression of ceruloplasmin in baboon and mouse lung during development and inflammation. Am J Respir Cell Mol Biol 1996;14:161–169.
7.
Kalmovarin N, Friedrichs WE, O’Brien HV, Linehan LA, Bowman BH, Yang F: Extrahepatic expression of plasma protein genes during inflammation. Inflammation 1991;15:369–379.
8.
Fleming RE, Whitman IP, Gitlin JD: Induction of ceruloplasmin gene expression in rat lung during inflammation and hyperoxia. Am J Physiol 1991;260:L68–L74.
9.
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R, and the Consensus Committee: Report of the American-European Consensus Conference on Acute Respiratory Distress Syndrome: Definitions, mechanisms, relevant outcomes and clinical trial coordination. J Crit Care 1994;9:72–81.
10.
Murray J F, Matthay MA, Luce JM, Flick MR: An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138:720–723.
11.
Kimura I, Moritani Y, Tanizaki Y: Basophils in bronchial asthma with reference to reagin-type allergy. Clin Allergy 1973;3:195–202.
12.
Out TA, Jansen HM, van Steenwijk RP, de Nooijer MJ, van de Graaf EA, Zuijderhoudt FMJ: ELISA of ceruloplasmin and α2-macroglobulin in paired bronchoalveolar lavage fluid and serum samples. Clin Chim Acta 1987;165:277–288.
13.
Delacroix DL, Marchandise FX, Francis C, Sibille Y: Alpha-2-macroglobulin, monomeric and polymeric immunoglobulin A and immunoglobulin M in bronchoalveolar lavage. Am Rev Respir Dis 1985;132:829–835.
14.
Holter JF, Weiland JE, Pacht ER, Gadeck JE, Davis WB: Protein permeability in the adult respiratory distress syndrome. Loss of size selectivity of the alveolar epithelium. J Clin Invest 1986;78:1513–1522.
15.
Gutteridge JM, Quinlan GJ, Evans TW: Transient iron overload with bleomycin detectable iron in the plasma of patients with adult respiratory distress syndrome. Thorax 1994;49:707–710.
16.
Bell DY, Haseman JA, Spock A, McLennan G, Hook GER: Plasma proteins of the bronchoalveolar surface of the lungs of smokers and nonsmokers. Am Rev Respir Dis 1981;124:72–79.
17.
Schoonbrood DFM, Lutter R, Habets FJM, Roos CM, Jansen HM, Out TA: Analysis of plasma-protein leakage and local secretion in sputum from patients with asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994;150:1519–1527.
18.
Gutteridge JMC, Mumby S, Quinlan GJ, Chung KF, Evans TW: Pro-oxidant iron is present in human pulmonary epithelial lining fluid: Implications for oxidative stress in the lung. Biochem Biophys Res Commun 1996;220:1024–1027.
19.
Kingston IB, Kingston BL, Putnam FW: Chemical evidence that proteolytic cleavage causes the heterogeneity present in human ceruloplasmin preparations. Proc Natl Acad Sci USA 1977;74:5377–5381.
20.
Lee CT, Fein AM, Lippmann M, Holzman H, Kimbel P, Weinbaum G: Elastolytic activity in pulmonary lavage fluid from patients with adult respiratory-distress syndrome. N Engl J Med 1981;304:192–196.
21.
McGuire WW, Spragg RG, Cohen AB, Cochrane CG: Studies on the pathogenesis of the adult respiratory distress syndrome. J Clin Invest 1982;69:543–553.
22.
Suter P, Suter S, Girardin E, Roux-Lombard P, Grau G, Dayer J: High bronchoalveolar lavage levels of tumour necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis 1992;145:1016–1022.
23.
Baker CS, Evans TW, Randle BJ, Haslam PL: Damage to surfactant-specific protein in acute respiratory distress syndrome. Lancet 1999;353:1232–1237.
24.
Stahl WM: Acute phase protein response to tissue injury. Crit Care Med 1987;15:545–550.
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2000
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