Hunting for a Pleural Fluid Test for Mesothelioma: Is Soluble Mesothelin the Answer?

EDITORIALS 561

Pleural fluid test for mesothelioma in pleural fluid from patients with

...... mesothelioma, metastatic carcinomas Thorax: first published as 10.1136/thx.2006.076612 on 28 June 2007. Downloaded from and benign asbestos pleural effusions. Scherpereel et al9 found a similar sensi- Hunting for a pleural fluid test for tivity (65%) for pleural fluid mesothelin with a specificity of 84%. To put this in mesothelioma: is soluble mesothelin the context, soluble mesothelin has a much more favourable sensitivity than other answer? tumour markers adopted in routine clinical practice, including prostate specific Y C Gary Lee antigen (21%),16 carcinoembryonic antigen (11%)17 and cancer antigen (CA)-125 ...... (57%)18 at similar specificity cut-off points (94–100%). In both studies the sensitivity of soluble n estimated 150 000 patients SOLUBLE MESOTHELIN IN mesothelin was limited by the lack of develop a pleural effusion each year MESOTHELIOMA reactivity in sarcomatoid tumours915 and Ain the UK. Establishing the aetiol- The Food and Drug Administration has some of the ‘‘mixed’’ mesotheliomas, pre- ogy of pleural effusions can be challen- recently approved the use of soluble sumablyoneswithaheavysarcomatoid ging as they can be associated with over mesothelin for disease monitoring in component. In both studies the sensitivity 50 systemic or pulmonary disorders.1 mesothelioma. This followed the findings and specificity were calculated using a cut- Exudative pleural fluids arise from of Robinson et al8 that blood levels of off value determined in the same cohort. plasma extravasation and contain pro- soluble mesothelin are significantly raised The cut-off values have not been tested in a teins and cells from the systemic circula- in patients with mesothelioma compared separate cohort to confirm the sensitivity tion, as well as those released locally from with controls with a wide range of and specificity. the pleura. This milieu of cellular pro- pleuropulmonary diseases. This observa- False positives also occur:5 soluble ducts potentially holds vital clues that can tion is robust and has been confirmed by mesothelin is released in significant unveil the underlying cause of the effu- other studies.9–11 Mesothelin is a 40 kDa quantities by ovarian and pancreatic sion. Decoding these clues has been a glycoprotein predominantly found in nor- carcinomas, as well as by a small propor- long and slow journey,2 and only in recent mal mesothelial cells in the pleura, tion of lung carcinomas and, in the years have several disease-specific pleural peritoneum and pericardium. Although current series, a patient with lymphoma.15 fluid markers been incorporated into mesothelin is bound to cell membrane, a Immunohistochemistry has revealed clinical practice (eg, adenosine deaminase circulating form termed soluble mesothe- mesothelin staining in several types of for tuberculous pleuritis3 and brain lin-related peptides (SMRP or ‘‘soluble non-mesothelioma cancers19 such as natriuretic peptide for effusions from mesothelin’’) has been found in the tumours of the gastrointestinal tract. It http://thorax.bmj.com/ cardiac failure). serum. It has been suggested that the is likely that some of these tumours will It is logical that diagnostic clues for protein may be a splice variant of the shed mesothelin into the blood or serosal mesothelioma, a primary pleural malig- normal mesothelin, with structural varia- fluids. Because of the significantly higher nancy, would rest within the pleural tion that alters its binding to cells.12 More incidence of malignant ascites from ovar- fluid. The incidence of mesothelioma is recently it has been suggested that SMRP ian carcinomas, the value of soluble rising significantly in the UK and other are mesothelin molecules released into mesothelin in peritoneal fluid as a diag- European countries. Most patients with the systemic circulation from malignant nostic marker for mesothelioma will be mesothelioma present with a pleural cells that overexpress mesothelin.13 14 lower than in pleural effusions. effusion, and this diagnosis should be Most (.95%) patients with mesothe- Pleural fluid levels of soluble mesothelin on September 29, 2021 by guest. Protected copyright. considered in all patients with exudative lioma have a pleural effusion; it would be were significantly higher than—but effusions. However, fluid cytology has a logical to assess the usefulness of soluble strongly correlated to—corresponding notoriously low diagnostic yield, as dif- mesothelin in pleural fluid as a diagnostic serum levels in the study by Creaney et ferentiating mesothelioma cells from test for mesothelioma. In this issue of al.15 This would be consistent with the belief benign (or reactive) mesothelial cells is Thorax, Creaney et al15 report that soluble that mesothelin is released from pleural difficult. More invasive procedures such mesothelin is detectable in pleural and mesothelioma cells into the pleural effusion as thoracoscopy for tissue biopsy samples peritoneal effusions and its levels are and probably absorbed subsequently into are frequently required.4 significantly higher (median 7-fold) in the systemic circulation. As such, pleural Finding a diagnostic marker for pleural mesothelioma (n = 52) than in fluid levels of soluble mesothelin may be a mesothelioma is a challenging endea- effusions of benign pleuritis (n = 84) and more sensitive test than serum levels in vour.5 This is made difficult by the non-mesothelioma malignancies (n = 56) diagnosing mesothelioma. Measurement of heterogeneity of mesothelioma, which (see page 569). Levels of soluble mesothe- soluble mesothelin levels in both pleural comprises various histological subtypes lin were also higher in ascitic fluid from fluid and serum may further increase the (eg, epithelioid, sarcomatoid, desmoplas- peritoneal mesothelioma than in benign sensitivity. tic) with dissimilar gene expression pat- controls. The level of soluble mesothelin, either in terns,6 phenotypes and biological Using a cut-off that yielded 98% speci- the blood or pleural fluid, did not predict features.4 No unique molecule has been ficity, the sensitivity of raised soluble survival when adjusted for the histology.815 shown to reliably define mesothelioma mesothelin in pleural fluid was 67% for However, it may reflect tumour load as a from benign mesothelium or metastatic all pleural mesothelioma and 77% for rapid reduction in mesothelin levels was carcinomas, even by profiling the expres- epithelioid mesothelioma. The results observed after debulking surgery for peri- sion of tens of thousands of genes on from the study by Creaney et al15 echoed toneal mesothelioma.10 Abiomarkerthat mesothelioma tissues using microarray those from a multicentre study from reflects the tumour response to mesothe- technology.7 France which compared mesothelin levels lioma treatment would be extremely

www.thoraxjnl.com 562 EDITORIALS useful, especially in research settings, as evidence towards a diagnosis of mesothe- 2 Lee YCG, Davies RJO, Light RW. Diagnosing pleural effusion: moving beyond transudate- radio-logical parameters are difficult to lioma in cases where the histopathology exudate separation. Chest 2007;131:942–3. Thorax: first published as 10.1136/thx.2006.076612 on 28 June 2007. Downloaded from follow in mesothelioma because of the is inconclusive or in patients unsuitable 3 Perez-Rodriguez E, Jimenez Castro D. The use of presence of effusions or prior pleurodesis. for invasive biopsies. adenosine deaminase and adenosine deaminase isoenzymes in the diagnosis of tuberculous pleuritis. These aspects of soluble mesothelin require Measuring the pleural fluid level of Curr Opin Pulm Med 2000;6:259–66. confirmation in large prospective studies. soluble mesothelin is convenient as most 4 West SD, Lee YCG. Current management of Interestingly, soluble mesothelin has patients will undergo thoracentesis in the malignant pleural mesothelioma. Clin Chest Med 2006;27:335–54. made its way into clinical practice as a investigation of their effusions. Soluble 5 Scherpereel A, Lee YCG. Biomarkers for biomarker when the biology of mesothe- mesothelin can be assayed in stored mesothelioma. Curr Opin Pulm Med lin is still relatively unknown. This effusion samples, which will allow clin- 2007;13 (in press). 6 Kettunen E, Nicholson AG, Nagy B, et al. L1CAM, molecule has a role in mediating cell icians to retrospectively request the test INP10, P-cadherin, tPA and ITGB4 over-expression adhesions, and strategies to antagonise should the initial investigation of the in malignant pleural mesotheliomas revealed by mesothelin have shown promise as inno- effusions fail to reveal a diagnosis. The combined use of cDNA and tissue microarray. 12 Carcinogenesis 2005;26:17–25. vative treatments for mesothelioma. commercially available enzyme-linked 7 Gordon GJ. Transcriptional profiling of Phase I trials of anti-mesothelin treat- immunoabsorbent assay has been shown mesothelioma using microarrays. Lung Cancer ment have been completed and more to be reliable for measurement of soluble 2005;49(Suppl 1):S99–103. advanced clinical trials are underway. 11 8 Robinson BWS, Creaney J, Lake R, et al. mesothelin. Mesothelin-family proteins and diagnosis of Targeting mesothelin may also allow the Soluble mesothelin is a useful marker for mesothelioma. Lancet 2003;362:1612–6. development of novel radiological ima- epithelioid mesothelioma but not for other 9 Scherpereel A, Grigoriu B, Conti M, et al. Soluble ging techniques to ‘‘home in’’ specifically mesothelin-related peptides in the diagnosis of histological variants of mesothelioma. The malignant pleural mesothelioma. Am J Respir Crit on the mesothelium and mesotheliomas. charge now is to seek an equivalent marker Care Med 2006;173:1155–60. for sarcomatoid mesothelioma to be used in 10 Hassan R, Remaley AT, Sampson ML, et al. Detection and quantitation of serum mesothelin, How would mesothelin fit into the combination with soluble mesothelin, a tumor marker for patients with mesothelioma diagnostic algorithm for exudative which will vastly enhance its clinical and ovarian cancer. Clin Cancer Res usefulness. Attempts to improve the diag- 2006;12:447–53. effusions? 11 Beyer HL, Geschwindt RD, Glover CL, et al. A definitive and watertight diagnosis of nostic yield by using better antibodies are MESOMARK: a potential test for malignant pleural 12 13 mesothelioma is important for determin- also underway. mesothelioma. Clin Chem 2007;53:666–72. An ideal diagnostic marker with perfect 12 Hassan R, Bera T, Pastan I. Mesothelin: a new ing treatment regimes (eg, pemetrexed) target for immunotherapy. Clin Cancer Res and securing compensation claims. accuracy will never be found. Soluble 2004;10:3937–42. Soluble mesothelin, with its limitations, mesothelin represents a significant step 13 Hellstrom I, Raycraft J, Kanan S, et al. Mesothelin towards the goal of diagnosing the cause variant 1 is released from tumor cells as a cannot replace histocytological diagnosis diagnostic marker. Cancer Epidemiol Biomarkers as the ‘‘gold standard’’. However, it may of pleural effusions without involving Prev 2006;15:1014–20. offer additional value to the existing invasive procedures. 14 Ho M, Onda M, Wang QC, et al. Mesothelin is diagnostic tests for pleural effusions. It shed from tumor cells. Cancer Epidemiol Thorax 2007;62:561–562. Biomarkers Prev 2006;15:1751. provides a significantly better sensitivity doi: 10.1136/thx.2006.076612 15 Creaney J, Yeoman D, Naumoff LK, et al. Soluble http://thorax.bmj.com/ than cytological examination. An mesothelin in effusions: a useful tool for the increased pleural fluid level of mesothe- Correspondence to: Dr Y C Gary Lee, Oxford diagnosis of malignant mesothelioma. Thorax Centre for Respiratory Medicine, Churchill 2007;62:569–76. lin, though not diagnostic on its own, Hospital, Oxford OX3 7LJ, UK; ycgarylee@ 16 Thompson IM, Ankerst DP, Chi C, et al. Operating would raise a strong suspicion of hotmail.com characteristics of prostate-specific antigen in men mesothelioma or metastatic (especially with an initial PSA level of 3.0 ng/ml or lower. Dr Lee is supported by a Wellcome Advanced JAMA 2005;294:66–70. ovarian or pancreatic) carcinomas and Fellowship and by project grants from the 17 Goldberg EM, Simunovic LM, Drake SL, et al. would help direct further investigations Medical Research Council (UK), British Lung Comparison of serum CA 19-9 and CEA levels in a population at high risk for colorectal cancer. (eg, thoracoscopy). Indeed, seven patients Foundation and NH&MRC (Australia). 15 Hybridoma 1989;8:569–75. on September 29, 2021 by guest. Protected copyright. in the study by Creaney et al had a raised 18 Helzlsouer KJ, Bush TL, Alberg AJ, et al. Prospective mesothelin level in their effusions up to study of serum CA-125 levels as markers of ovarian 10 months before the diagnosis was cancer. JAMA 1993;269:1123–6. REFERENCES 19 Ordonez NG. Value of mesothelin immunostaining established. A raised soluble mesothelin 1 Light RW, Lee YCG. Textbook of pleural diseases. in the diagnosis of mesothelioma. Mod Pathol level may also provide supportive London: Arnold Press, 2003. 2003;16:192–7.

www.thoraxjnl.com EDITORIALS 563

Pulmonary coagulopathy Ventilator-induced coagulopathy

...... Compelling evidence from preclinical and Thorax: first published as 10.1136/thx.2006.076612 on 28 June 2007. Downloaded from clinical studies shows that mechanical ventilation aggravates or may even initiate Pulmonary coagulopathy: a potential lung injury.17 18 The similarities between the inflammatory responses in pneumonia and therapeutic target in different forms of ALI/ARDS suggest that similar changes in coagulation and fibrinolysis may occur in lung injury ventilator-induced lung injury. The knowl- edge on ventilator-induced coagulopathy is Marcus J Schultz, Marcel Levi rapidly growing. Several preclinical studies and one clinical study in healthy subjects ...... suggest that pulmonary fibrin turnover is indeed influenced by mechanical ventila- The role and source of tissue factor tion.19–21 Some suggestion on the existence of TF-mediated coagulation caused by large body of evidence has shown tion. The profile and extent of these mechanical ventilation comes from a pre- that systemic coagulopathy is a key changes vary with the severity of inflam- liminary report on short-term mechanical event in severe systemic inflamma- mation: in severe pneumonia demanding ventilation in patients undergoing a surgi- A 1 21 tion, such as that which occurs in sepsis. mechanical ventilation the changes are cal procedure. In addition, small but Systemic coagulopathy is the net result of nearly identical to those in ARDS,56while consistent changes in pulmonary coagula- activation of coagulation and defective less prominent alterations of alveolar tion in mice have been found with injurious systems of natural inhibition of coagula- fibrin turnover have been measured in forms of mechanical ventilation (Wolthuis, tion, on the one hand, and attenuation of spontaneously breathing patients with unpublished data). Only two preclinical fibrinolysis on the other. Activation of pneumonia.5 The mechanisms that con- studies have focused on the effect of coagulation is primarily driven by the tribute to disturbed alveolar fibrin turn- mechanical ventilation on pulmonary fibri- extrinsic coagulation pathway which over are not clearly understood, but are nolysis,19 20 in which it was found that starts with expression of tissue factor thought to be similar to those found in injurious mechanical ventilation attenuates (TF) on mononuclear cells and endothe- the intravascular spaces during severe fibrinolytic activity in rats, which appears lial cells. TF then binds and activates systemic inflammation.7–9 Similar to sep- to be caused by increased production and/ factor VII which activates downstream sis, in ARDS and pneumonia alveolar or release of PAI-1. coagulation cascades.23Mechanisms that thrombin generation seems to be regulate the coagulation pathway under mediated by the TF–factor VIIa pathway. SOURCE OF TF IN ALVEOLAR normal conditions involve natural inhibi- Patients who develop ventilator-asso- SPACES tors of coagulation, including activated ciated pneumonia have increased bronch-

One limitation with all studies on pulmon- http://thorax.bmj.com/ protein C (APC), antithrombin (AT) and oalveolar levels of soluble TF and factor ary coagulopathy so far is that they do not tissue factor pathway inhibitor (TFPI). In VII.9 In patients with ARDS an increase in give sufficient insight into the potential general, they all interfere with the TF– soluble TF, factor VIIa and TF-dependent sources of TF in the alveolar spaces. It has factor VIIa-induced activation of coagula- factor X activation in bronchoalveolar been suggested that changes in coagulation tion, but on different levels. In patients lavage (BAL) fluid has been demon- and fibrinolysis found in the pulmonary with sepsis, increased coagulant activity strated. In addition, inhibition of the compartmentaretheresultofleakageof is not sufficiently counterbalanced by TF–factor VIIa pathway completely abro- coagulation factors into the lungs from the these natural inhibitors. In addition, a gated intrapulmonary fibrin deposition in systemic circulation. Indeed, concordant rapid sustained increase in synthesis of 10 on September 29, 2021 by guest. Protected copyright. patients with ARDS. Although the lung increased activation of coagulation in the plasminogen activator inhibitor (PAI)-1 is has only a limited capacity to produce systemic compartment was found with present during the septic response. PAI-1 11 protein C, APC is present in BAL fluid. infectious pulmonary coagulopathy in one is the main inhibitor of tissue-type and The protein C system has been shown to study.9 However, TF is not present in the urokinase-type plasminogen activator be suppressed in patients with ventilator- systemic circulation. In addition, pulmon- (tPA and uPA) which activate the fibri- 12 13 associated pneumonia and pulmonary ary infection was characterised by local nolytic system. The importance of sys- 14 inflammation. In association with (but not systemic) attenuation of fibrino- temic coagulopathy with sepsis has been enhanced fibrin production, fibrinolytic lysis, suggesting that pulmonary coagulo- established in experimental studies and activity is depressed in BAL fluid of pathy is a localised process. in the randomised, prospective, double- 5 patients with ALI/ARDS or pneumonia, In this issue of Thorax, Bastarache et al22 blind, placebo-controlled PROWESS trial related to high pulmonary concentrations report their findings on the ability of the in which infusion of recombinant human of PAI-1. PAI-1 is increased in ALI/ARDS alveolar epithelium to initiate intra-alveo- (rh)-APC resulted in improved survival of and is probably secreted by lung epithelial lar coagulation by expressing active TF patients with severe sepsis.4 cells, fibroblasts and endothelial cells.15 16 (see page 608). Using an in vitro cell Patients at risk of ventilator-associated surface TF assay and TF ELISA, they LOCAL COAGULOPATHY WITH pneumonia show similar changes in measured the production and activity of ACUTE LUNG INJURY pulmonary fibrin turnover.9 The impor- TF in cultured alveolar epithelial cells Coagulopathy with acute lung injury tant role of the fibrinolytic system in the following exposure to different stimuli. and/or pneumonia pathogenesis of pneumonia is under- TF activity, mRNA and protein levels Recent studies have clearly shown that scored by the observation that the depres- increased in A549 cells after stimulation prominent changes in local fibrin turnover sion of bronchoalveolar fibrinolysis with a pro-inflammatory stimulus (cyto- are an important feature of acute lung precedes the clinical occurrence of venti- mix). Importantly, increased TF activity injury (ALI)/acute respiratory distress lator-associated pneumonia by several was also measured following incubation syndrome (ARDS) and pulmonary infec- days.9 with pulmonary oedema fluid from

www.thoraxjnl.com 564 EDITORIALS patients with ALI/ARDS. Furthermore, CONCLUSION respiratory distress syndrome. Am J Physiol 1991;261:L240–8. immunohistochemistry for TF in human Alveolar fibrin deposition is an important 9 Schultz MJ, Millo J, Levi M, et al. Local activation of Thorax: first published as 10.1136/thx.2006.076612 on 28 June 2007. Downloaded from lung tissue from patients with ALI/ARDS feature of pulmonary infection or inflam- coagulation and inhibition of fibrinolysis in the lung showed prominent TF staining in alveolar mation. Some studies also suggest that during ventilator associated pneumonia. Thorax 2004;59:130–5. epithelial cells as well as intra-alveolar pulmonary coagulopathy is a feature of 10 Miller DL, Welty-Wolf K, Carraway MS, et al. macrophages and hyaline membranes. ventilator-induced lung injury. Extrinsic coagulation blockade attenuates lung Given the markedly increased levels in Mechanisms that contribute to this fibrin injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. Am J Respir Cell pulmonary oedema fluid compared with deposition are localised thrombin genera- Mol Biol 2002;26:650–8. plasma, it strongly suggests that there is tion and depression of bronchoalveolar 11 Yamamoto K, Loskutoff DJ. Extrahepatic expression an intra-alveolar source of TF. The fibrinolysis. Remarkably, changes in and regulation of protein C in the mouse. reported findings further provide convin- alveolar coagulation and fibrinolysis clo- Am J Pathol 1998;153:547–55. 12 Choi G, Schultz MJ, Levi M, et al. Protein C in cing evidence that the alveolar epithelium sely resemble those found systemically in pneumonia. Thorax 2005;60:705–6. can initiate TF-dependent intra-alveolar patients with sepsis. Recent studies have 13 Choi G, Bresser P, Levi M, et al. Disturbed alveolar coagulation in this disease setting. The demonstrated the beneficial effect of fibrin turnover during pneumonia is associated with reduced activated protein C levels in lungs. Crit major strengths of the study include the anticoagulant therapy in sepsis. Care 2004;8(Suppl 1):111. use of a well-characterised and large Theoretical considerations suggest novel 14 Hataji O, Taguchi O, Gabazza EC, et al. Activation cohort of patients with ALI/ARDS with therapeutic strategies or preventive mea- of protein C pathway in the airways. Lung 2002;180:47–59. an appropriate control group, the use of sures in critically ill patients, but clinical 15 Idell S. Endothelium and disordered fibrin turnover co-staining with a type II epithelial cell studies are needed to examine this in the injured lung: newly recognized pathways. marker in the immunohistochemical stu- hypothesis. Crit Care Med 2002;30:S274–80. 16 Marshall BC, Sageser DS, Rao NV, et al. Alveolar dies and the fact that TF measurements Thorax 2007;62:563–564. epithelial cell plasminogen activator. were performed on undiluted pulmonary doi: 10.1136/thx.2006.067256 Characterization and regulation. J Biol Chem oedema fluid rather than using BAL fluid, 1990;265:8198–204. 17 Belperio JA, Keane MP, Burdick MD, et al. Critical thus avoiding potential complications due ...... role for CXCR2 and CXCR2 ligands during the to dilution effects. One weakness of the Authors’ affiliations pathogenesis of ventilator-induced lung injury. J Clin study is that the investigators did not Marcus J Schultz, Department of Intensive Care Invest 2002;110:1703–16. Medicine and Laboratory of Experimental 18 Altemeier WA, Matute-Bello G, Frevert CW, et al. study alveolar macrophages, as it has Mechanical ventilation with moderate tidal volumes been shown that alveolar macrophages Intensive Care and Anesthesiology (LEICA), synergistically increases lung cytokine response to from humans contain procoagulant activ- Academic Medical Center - University of systemic endotoxin. Am J Physiol Lung Cell Mol ity.23 Also, they did not consider the Amsterdam, and HERMES Critical Care Group, Physiol 2004;287:L533–42. Amsterdam, The Netherlands 19 Dahlem P, Bos AP, Haitsma JJ, et al. Alveolar pulmonary vascular endothelium as a Marcel Levi, Department of Internal Medicine, fibrinolytic capacity suppressed by injurious mechanical ventilation. Intensive Care Med potential source of TF during pulmonary Academic Medical Center - University of inflammation. 2005;31:724–32. Amsterdam, Amsterdam, The Netherlands 20 Dahlem P, Bos AO, Haitsma JJ, et al. Mechanical ventilation affects alveolar fibrinolysis in LPS- induced lung injury. Eur Respir J 2006;28:992–8. CLINICAL CONSIDERATIONS Correspondence to: Dr Marcus J Schultz, 21 Choi G, Wolthuis E, Bresser P, et al. Mechanical http://thorax.bmj.com/ Infusion of rh-APC has been found to Department of Intensive Care Medicine, C3-415, ventilation with lower tidal volumes and positive Academic Medical Center, Meibergdreef 9, end-expiratory pressure prevents alveolar reduce mortality of patients with severe 1105 AZ Amsterdam, The Netherlands; 4 coagulation in patients without lung injury. sepsis. Many patients included in this trial [email protected] Anesthesiology 2006;105:689–95. had concomitant ARDS, and many had Competing interests: None. 22 Bastarache J, Wang L, Geiser T, et al. The alveolar pneumonia as the primary source of epithelium can initiate the extrinsic coagulation 24 cascade through expression of tissue factor. Thorax sepsis. One can hypothesise that the 2007;62:608–16. beneficial effect of APC was the result, at REFERENCES 23 Lyberg T, Nakstad B, Hetland O, et al. least in part, of APC on intra-alveolar Procoagulant (thromboplastin) activity in human

1 Levi M, Ten Cate H. Disseminated intravascular bronchoalveolar lavage fluids is derived from on September 29, 2021 by guest. Protected copyright. coagulopathy. Indeed, rh-APC exerts anti- coagulation. N Engl J Med 1999;341:586–92. alveolar macrophages. Eur Respir J 1990;3:61–7. coagulant effects in the human lung 2 Levi M, ten Cate H, Bauer KA, et al. Inhibition of 24 Laterre P-F, Garber G, Levy H, et al. Severe challenged with endotoxin:25 activation of endotoxin-induced activation of coagulation and community-acquired pneumonia as a cause of fibrinolysis by pentoxifylline or by a monoclonal severe sepsis: data from the PROWESS study. Crit coagulation after pulmonary challenge anti-tissue factor antibody in chimpanzees. J Clin Care Med 2005;33:952–61. with endotoxin is inhibited and increased Invest 1994;93:114–20. 25 van der Poll T, Levi M, Nick JA, et al. Activated PAI-1 activity is diminished by infusion of 3 Giesen PL, Rauch U, Bohrmann B, et al. Blood- protein C inhibits local coagulation after rh-APC. Thus, systemic administration of borne tissue factor: another view of thrombosis. intrapulmonary delivery of endotoxin in humans. Proc Natl Acad Sci USA 1999;96:2311–5. Am J Respir Crit Care Med 2005;171:1125–8. APC influences pulmonary fibrin turnover. 4 Bernard GR, Vincent JL, Laterre PF, et al. Efficacy 26 Desai MH, Mlcak R, Richardson J, et al. Reduction Clinical trials in ALI/ARDS have pri- and safety of recombinant human activated protein in mortality in pediatric patients with inhalation marily targeted inflammation and not C for severe sepsis. N Engl J Med injury with aerosolized heparin/N-acetylcystine 2001;344:699–709. [correction of acetylcystine] therapy. J Burn Care coagulation, although nebulisation of 5 Gunther A, Mosavi P, Heinemann S, et al. Alveolar Rehabil 1998;19:210–2. heparin has been found to be beneficial fibrin formation caused by enhanced procoagulant 27 Brown M, Desai M, Traber LD, et al. and depressed fibrinolytic capacities in severe Dimethylsulfoxide with heparin in the treatment of in preclinical and clinical studies in pneumonia. Comparison with the acute respiratory 26–30 smoke inhalation injury. J Burn Care Rehabil patients with inhalation trauma. The distress syndrome. Am J Respir Crit Care Med 1988;9:22–5. results from new studies on interventions 2000;161:454–62. 28 Cox CS Jr, Zwischenberger JB, Traber DL, et al. on (alveolar) fibrin turnover with TFPI 6 Fuchs-Buder T, de Moerloose P, Ricou B, et al. Time Heparin improves oxygenation and minimizes course of procoagulant activity and D dimer in barotrauma after severe smoke inhalation in an and rh-APC are presently awaited. In bronchoalveolar fluid of patients at risk for or with ovine model. Surg Gynecol Obstet view of the results from the study by acute respiratory distress syndrome. Am J Respir 1993;176:339–49. Bastarache et al,22 epithelial-directed Crit Care Med 1996;153:163–7. 29 Murakami K, McGuire R, Cox RA, et al. Heparin 7 Idell S, Gonzalez K, Bradford H, et al. Procoagulant nebulization attenuates acute lung injury in sepsis treatment that could be delivered by activity in bronchoalveolar lavage in the adult following smoke inhalation in sheep. Shock inhalation of nebulised anticoagulant or respiratory distress syndrome. Contribution of tissue 2002;18:236–41. profibrinolytic agents seems an attractive factor associated with factor VII. Am Rev Respir Dis 30 Saliba MJ Jr. The effects and uses of heparin in 1987;136:1466–74. the care of burns that improves treatment and approach in treating patients with or at 8 Idell S, Koenig KB, Fair DS, et al. Serial enhances the quality of life. Acta Chir Plast risk of pulmonary coagulopathy. abnormalities of fibrin turnover in evolving adult 1997;39:13–6. www.thoraxjnl.com