ArticlesPrediction of lung-transplant rejection by hepatocyte growth factor
Introduction
There has been much progress in lung transplantation since its inception.1, 2, 3, 4 At present, chronic obstructive pulmonary diseases (COPD), including emphysema and α1-antitrypsin deficiency syndrome, are the most common indications for lung transplantation, followed by cystic fibrosis, idiopathic pulmonary fibrosis, and primary pulmonary hypertension.3, 4, 5 The most important causes of morbidity and mortality in lung transplantation are primary graft failure, infection, and acute and chronic rejection.4 Surveillance protocols involving transbronchial lung biopsies have shown that most transplant recipients have at least one episode of acute rejection; the frequency is greatest during the first 100 days after transplantation. 4, 6, 7
Clinical criteria alone are imprecise for diagnosis of rejection. Examination of a tissue sample obtained by transbronchial biopsy can diagnose graft rejection, but the procedure is invasive and cannot be done repeatedly.7 Morbidity and mortality are increased if early rejection is missed, so markers of rejection are being sought. An ideal marker would be obtainable non-invasively; measurable repeatedly, easily, and quickly; sensitive and specific; and inexpensive. A serological marker would best fit these criteria and could complement clinical features7 for more accurate and rapid recognition of graft rejection. Serum adhesion molecules and bronchoalveolar lavage markers have proved to be disappointing markers,8, 9, 10 and none has become a standard test.
Hepatocyte growth factor (HGF) was first detected in the plasma of partially hepatectomised rats11 and later purified from human plasma and lung fibroblasts.12, 13 In addition to its role in regeneration of injured lung,14 HGF acts in other organs. Studies in animals ssuggest that it is a sensitive measure of kidney-graft rejection.15, 16 Whether HGF can identify lung-graft rejection is unknown. We have investigated this issue.
Section snippets
Patients
We included in this study, which was approved by the institutional ethics committee, 109 patients undergoing lung transplantation who gave informed consent to participate (table 1). 12 healthy volunteers served as controls. Serum samples were collected and coded before and after lung transplantation, daily for the first week, then every 2 days from week 2 to week 5, then weekly to 24 weeks after transplantation. One serum sample was obtained from each control. Episodes of rejection and
Results
The mean serum HGF concentration was 645 ng/L (SD 259) in controls. Before transplantation the mean concentration was 1457 ng/L (703) in patients with COPD, 1401 ng/L (572) in those with cystic fibrosis, and 1217 ng/L (533) in those with idiopathic lung fibrosis (no significant difference); the overall mean in all patients was 1358 ng/L (603). To elucidate how serum concentrations of HGF change after lung transplantation, we plotted the concentrations over time in all patients who had no events
Discussion
Many studies have focused on the roles of cytokines and growth factors in development of inflammatory responses,18 graft dysfunction,19 and graft rejection20 after lung transplantation. There is some evidence that serum concentrations of certain interleukins are increased during early haemodynamic failure after lung transplantation.18 Transforming growth factor β might be important in chronic lung graft rejection with bronchiolitis obliterans, because concentrations of its mRNA are increased in
References (28)
- et al.
The Registry of the International Society for Heart and Lung Transplantation: sixteenth official report, 1999
J Heart Lung Transplant
(1999) - et al.
Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation
J Thorax Cardiovasc Surg
(1995) - et al.
Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats
Biochem Biophys Res Commun
(1984) - et al.
Hepatocyte growth factor may act as a pulmotrophic factor on lung regeneration after acute lung injury
J Biol Chem
(1993) - et al.
Hepatocyte growth factor: a sensitive indicator for the acute rejection of renal transplants
Transplant Proc
(2000) - et al.
Early release of proinflammatory cytokines after lung transplantation
Chest
(1998) - et al.
Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation
J Heart Lung Transplant
(1999) - et al.
Lung allograft dysfunction correlates with gamma-interferon gene expression in bronchoalveolar lavage
J Heart Lung Transplant
(1999) - et al.
Combination prophylaxis with ganciclovir and cytomegalovirus (CMV) immune globulin after lung transplantation: effective CMV prevention following daclizumab induction
Am J Transplant
(2003) - et al.
Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distal organs
Biochem Biophys Res Commun
(1992)
Unilateral lung transplantation for pulmonary fibrosis
N Engl J Med
for the Toronto Lung Transplant Group. Results of single-lung transplantation for bilateral pulmonary fibrosis
N Engl J Med
Results of bilateral lung transplantation
Lung transplantation
N Engl J Med
Cited by (33)
Lung Transplant Pathology: An Overview on Current Entities and Procedures
2020, Surgical Pathology ClinicsPretransplant serum human chitinase-like glycoprotein YKL-40 concentrations independently predict bronchiolitis obliterans development in lung transplant recipients
2014, Journal of Thoracic and Cardiovascular SurgeryCitation Excerpt :The pathogenesis of BOS is not clearly understood; however, the existing evidence on the role of small airway inflammation and acute rejection in BOS strongly suggests that the cellular and humoral storm directed to the allograft is crucial in the pathogenesis of BOS.6 Toward this end, we and others have shown that several growth factors and cytokines are involved in BOS pathogenesis.8,15-17 Our study shows that YKL-40 is elevated in BOS patients and its levels well correlate with BOS severity.
Biomarkers of pulmonary rejection
2013, Transplantation ProceedingsAcute Allograft Rejection: Cellular and Humoral Processes
2011, Clinics in Chest MedicineCitation Excerpt :Even more attractive are studies of noninvasive means of diagnosing acute rejection without bronchoscopy. Although no effective serum biomarkers are currently in use in clinical lung transplant, many have been studied, and some, such as the hepatocyte growth factor, have been shown to correlate with acute rejection in small single-center studies.30 In 2002, the Cylex Immune Cell Function Assay (ImmuKnow; Cylex, Incorporated, Columbia, MA, USA) was approved by the US Food and Drug Administration to measure global immune function in solid organ transplant recipients.
Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients
2010, Journal of Thoracic and Cardiovascular SurgeryCitation Excerpt :The TBB specimens were also histologically screened for CMV, pneumocystis carinii, toxoplasmosis, and bacterial or invasive fungal infection. Colonization was considered present if the BAL microbiology was positive without histologic or clinical evidence of infection.16 The immunosuppression protocol has been previously described.16
Intermediate and Late Complications of Lung Transplantation
2010, Medical Management of the Thoracic Surgery Patient