Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation.
(65/382)
Bronchiolitis obliterans syndrome (BOS) is a severe complication after lung transplantation (LTX). In a retrospective cohort study 12 stable healthy recipients (non-BOS) and eight patients with BOS were enrolled after LTX and matrix metalloproteinases (MMP)-9, TIMP-1 and cell characteristics in bronchoalveolar lavage (BAL) samples (n = 145) were analysed. BALs from patients with BOS were further divided according to whether they were obtained before (pre-BOS) or after manifestation of BOS (BOS group). The MMP-9/TIMP-1 ratio was significantly increased in the BOS group compared with non-BOS or pre-BOS; furthermore, the ratio was negatively correlated with forced expiratory volume in one second. In zymography, the active form of MMP-9 was detected predominantly in the BOS group. In addition, zymography showed the banding pattern of neutrophil-derived MMP-9, indicating that polymorphonuclear neutrophils (PMNs) were the main source of MMP-9. According to that, MMP-9 was significantly correlated with the number of PMN. In immunocytochemistry, MMP-9 was also associated predominantly with PMN. This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 over time during manifestation of a fibroproliferative lung disease in patients. It demonstrates development of bronchiolitis obliterans syndrome after lung transplantation is associated with an imbalance of matrix metalloproteinases-9/tissue inhibitors of metalloproteinase-1 ratio. (+info)
Inhibition of obliterative airway disease development in murine tracheal allografts by matrix metalloproteinase-9 deficiency.
(66/382)
This study was designed to define the roles of matrix metalloproteinase (MMP)-2 and MMP-9 in obliterative airway disease (OAD) in heterotopic murine tracheal allografts, considered a suitable animal model for chronic lung allograft rejection. BALB/c tracheal allografts were transplanted into MMP-2-deficient (-/-) and MMP-9-/- mice. Also, wild-type recipients were treated with doxycycline, a nonspecific MMP inhibitor. After 10, 20 and 30 days, allografts were analyzed for OAD development, intragraft levels of MMP-2 and MMP-9 and the frequency and cytokine/chemokine production profile of alloreactive T cells. Allografts transplanted into wild-type mice developed OAD lesions within 30 days. These allografts revealed significant upregulation of both MMP-2 and MMP-9. Allografts transplanted into MMP-9-/- and doxycycline-treated recipients did not develop OAD. In contrast, allografts transplanted into MMP-2-/- mice developed OAD lesions with normal kinetics. Interestingly, MMP-9-/- recipients showed an enhanced T cell alloreactivity associated with an abnormal profile of cytokine/chemokine production. The enhanced T cell alloreactivity in MMP-9-/- mice was mediated by enhanced dendritic cell stimulatory capacity as well as enhanced T cell responsive capacity. These results suggest that MMP-9 plays an important role in the pathogenesis of OAD and may represent a target for the therapeutic intervention of chronic lung allograft rejection. (+info)
Functional status and quality of life in patients surviving 10 years after lung transplantation.
(67/382)
Although many lung allograft recipients achieve long-term survival, there is a lack of published data regarding these patients' functional status and quality of life (QoL). We evaluated all 10-year survivors at our institution and, utilizing the SF-36 questionnaire, compared their QoL to population normative and chronic illness data. Twenty-eight (29%) of 96 patients survived > or =10 years following 11 single, 6 bilateral and 11 heart-lung procedures. At the most recent evaluation, median FEV(1) in single and double lung recipients was predicted to be 54% and 74%, respectively. Five (18%) patients had BOS score 0, 13 (46%) BOS 1, 5 (18%) BOS 2 and 5 (18%) BOS 3 and median time to BOS was 7 years. Four (14%) patients required renal replacement therapy. Three patients (11%) developed symptomatic osteoporosis, 2 (7%) post-transplant lymphoma and 1 (4%) an ischaemic stroke. Scores for physical function, role-physical/emotional and general health, but not mental health and bodily pain, were significantly lower compared to normative and chronic illness data. Energy and social-function scores were significantly lower than normative data alone. Long-term survival after lung transplantation is characterized by an absence or delayed development of BOS, low iatrogenic morbidity and preserved mental, but reduced physical health status. (+info)
Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome.
(68/382)
Bronchiolitis obliterans syndrome (BOS) remains the leading cause of morbidity/mortality following lung transplantation. In recipients with BOS, markers predicting the decline in lung function are needed. The aim of this longitudinal study was to determine whether exhaled nitric oxide fraction (FeNO) measurements provide useful information for discriminating patients with unstable BOS from those with stable BOS. During a 14-month period, 145 FeNO measurements were performed in 50 lung transplant recipients. Among them, 16 recipients with BOS (32 FeNO measurements) were analysed. For each FeNO measurement, the patients were classified into three groups according to the decline in forced expiratory volume in one second (FEV1) within the following 6 months: 1) stable BOS free; 2) stable BOS (decline in FEV1 of <5%); and 3) unstable BOS (decline in FEV1 of > or =15%). The mean FeNO in patients with unstable BOS was significantly increased compared with that in stable BOS-free patients (18.4+/-5.7 versus 9.7+/-3.7 ppb) and that in patients with stable BOS (18.4+/-5.7 versus 9.7+/-3.3 ppb). The present findings suggest that, in patients with bronchiolitis obliterans syndrome, a raised exhaled nitric oxide fraction may predict the development of worrisome functional impairment during long-term follow-up. (+info)
Chemokine-mediated angiogenesis: an essential link in the evolution of airway fibrosis?
(69/382)
Angiogenesis may be an important factor in the development of fibrotic lung disease. Prior studies have strongly suggested a role for angiogenic vascular remodeling in pulmonary fibrosis, and emerging evidence indicates that new vessel formation is critical in airway fibrosis. Bronchiolitis obliterans syndrome is a fibrotic occlusion of distal airways that is largely responsible for the morbidity and mortality of patients after lung transplantation. In this issue, Belperio et al. demonstrate a role for CXC chemokine receptor 2 in the regulation of angiogenesis-mediated airway fibroproliferation. By integrating an understanding of neovascularization into the study of events that occur between inflammation and fibrosis, it becomes increasingly possible to rationally design therapies that can halt conditions of maladaptive fibrosis. (+info)
Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.
(70/382)
Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment. (+info)
Broncho-alveolar lavage matrix metalloproteases as a sensitive measure of bronchiolitis obliterans.
(71/382)
Bronchiolitis obliterans (BO) is a survival-limiting factor in lung transplantation. There are no common BO markers in use. Since BO is associated with extracellular matrix remodeling, we asked whether matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) could serve as BO markers. In 72 lung transplant patients (34 BO syndrome (BOS) 0, 15 BOS 0-p, and 23 BOS 1) serum and broncho-alveolar lavage (BAL) MMP and TIMP levels were examined by ELISA. The BAL cell counts were additionally analyzed. The serum MMP-2, MMP-8, MMP-9 and TIMP-2 levels were not different in all groups. In contrast, the BAL MMP-8, -9 and TIMP-1 levels were significantly elevated in BOS 0-p (p = 0.003; p = 0.007; p = 0.0003, respectively) and BOS 1 (p = 0.003; p = 0.001; p = 0.0004, respectively) as compared to BOS 0 patients. The BAL MMP-8, -9 and TIMP-1 levels were significant predictors of BOS 0-p (p = 0.01; p = 0.01; p = 0.01, respectively) and BOS-1 (p = 0.007; p = 0.01; p = 0.006, respectively) in receiver operating characteristic analysis. Except for BAL macrophages that were significantly decreased in BOS 0-p versus BOS 0 patients; other cell counts were not different between the groups. BAL MMP-8, -9 and TIMP-1 might be useful markers to detect BO in lung transplant patients. (+info)
Prognostic value of bronchiolitis obliterans syndrome stage 0-p in single-lung transplant recipients.
(72/382)
RATIONALE: Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV(1) and forced expiratory flow, midexpiratory phase (FEF(25-75%)), has been proposed, there is a paucity of data validating its utility in single-lung transplantation. OBJECTIVE: The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation. METHODS: We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology. RESULTS: BOS 0-p FEV(1) was associated with higher sensitivity, specificity, and positive predictive value than the FEF(25-75%) criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV(1) in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV(1) in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV(1) criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV(1) were significantly different between patients with underlying restrictive versus obstructive physiology (p = 0.05 and 0.01, respectively). CONCLUSION: The FEV(1) criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF(25-75%) criterion. (+info)