Lymph node dissection in thymic carcinomas and neuroendocrine carcinomas.

OBJECTIVES: Although lymph node (LN) metastases are not uncommon in thymic carcinomas, preoperative LN evaluation, intraoperative lymph node dissection (LND) and postoperative outcomes remain unknown. The aim of this study was to elucidate the characteristics of and outcomes in patients with thymic carcinomas and thymic neuroendocrine carcinomas undergoing LND. METHODS: A retrospective chart review was performed using our multi-institutional database to identify patients who underwent resection and LND for thymic carcinoma or thymic neuroendocrine carcinoma between 1991 and 2018. An enlarged mediastinal LN was defined as having a short-axis diameter >1 cm. We assessed survival outcomes using the Kaplan-Meier analysis. RESULTS: N1-level LND was performed in 41 patients (54.6%), N2-level LND in 14 patients (18.7%) and both-level LND in 16 patients (21.3%). Pathological LN metastasis was detected in 20 patients (26.7%) among the 75 patients undergoing LND. There was a significant difference in the number of LN stations (P = 0.015) and metastasis factor (P = 0.0042) between pathologically LN-positive and pathologically LN-negative patients. The sensitivity of enlarged LNs on preoperative computed tomography was 18.2%. There was a tendency towards worse overall survival of pathologically N2-positive patients, although the difference was not statistically significant (P = 0.15). CONCLUSIONS: Preoperative CT appears to play a limited role in detecting pathological LN metastases. Our findings suggest that the significance of N1- and N2-level LND should be evaluated in prospective studies to optimize the postoperative management of patients with thymic carcinomas and neuroendocrine carcinomas.

Are volume-dependent parameters in positron emission tomography predictive of postoperative recurrence after resection in patients with thymic carcinoma?

This study aimed to investigate the association between the volume-dependent parameters in 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) and a recurrence of thymic carcinoma. A retrospective chart review was performed based on our multi-institutional database to identify patients undergoing PET prior to resection of thymic carcinoma or neuroendocrine carcinoma between 1991 and 2018. The PET parameters (metabolic tumor volume and total lesion glycolysis) were evaluated retrospectively. The relevant factors were extracted and a survival analysis was performed using the Kaplan-Meier method. Sixteen patients were thus deemed to be eligible for analysis. The median follow-up period following resection was 2.65 years (range: 0.96-0.68 years). The recurrence-free survival was significantly longer in patients with a metabolic tumor volume < = 22.755 cm3 and with total lesion glycolysis < = 105.4006 g/mL (p = 0.001 and 0.001, respectively, by a log-rank test). The metabolic tumor volume and total lesion glycolysis may, therefore, be predictive of the postoperative recurrence of thymic carcinoma.

The treatment and survival of patients with postoperative recurrent thymic carcinoma and neuroendocrine carcinoma: a multicenter retrospective study.

PURPOSE: There are few data available on the outcomes of postoperative recurrent thymic carcinoma (TC) and thymic neuroendocrine carcinoma (TNEC). The aim of this study is to evaluate the treatment and survival in patients with recurrent TC and TNEC after undergoing surgical resection. METHODS: A retrospective chart review was performed using our multicenter database to identify patients with a postoperative recurrence of TC and TNEC from 1995 to 2018. The clinicopathological factors were reviewed and the survival outcomes were analyzed. RESULTS: Sixty patients were identified among 152 patients who underwent resection of TC and TNEC. The median follow-up period from the first recurrence was 14.8 months (range 0-144). The 5-year post-recurrence survival was 23% for the whole cohort. According to a univariable analysis, advanced stage [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.09-9.54], interval between primary surgery and recurrence (HR 0.97, 95% CI 0.95-0.99), any treatment for recurrence (HR: 0.27, 95% CI 0.13-0.58) and chemotherapy for recurrence (HR: 0.46, 95% CI 0.22-0.95) were significant factors related to post-recurrence survival. CONCLUSIONS: Chemotherapy rather than surgery appears to be the mainstay treatment for managing patients with postoperative recurrent TC and TNEC and it may also be considered in multidisciplinary management. Further studies with a larger sample size are required to confirm our findings.

Survival outcomes of patients with high-grade and poorly differentiated thymic neuroendocrine carcinoma.

High-grade and poorly differentiated thymic neuroendocrine carcinoma is the rarest entity in thymic epithelial tumours. The aim of this study is to report survival data in a multi-institutional database in comparison to data in the literature. Retrospective chart review was performed on the basis of our multi-institutional database to identify patients undergoing the resection of poorly differentiated thymic neuroendocrine carcinoma between 1991 and 2018. Relevant factors were extracted, and survival analysis was performed using the Kaplan-Meier method. Twenty-one patients were identified. Five-year overall survival and recurrence-free survival were 64.6% and 51.8%, respectively. Twelve (57.1%) patients had recurrences. Due to the scarcity of data reported in the literature, our data may be used as a standard in high-grade and poorly differentiated thymic neuroendocrine carcinoma.

[Synchronous Multicentric Thymoma].

A 76-year-old man was referred to our hospital because of an abnormal shadow on chest X-ray. His physical exams and laboratory data were not notable. Chest computed tomography (CT) showed 2 nodular lesions with clear margin in anterior mediastinum. The nodule at the left inferior pole of the thymus was 9 cm in diameter, and another one at the right inferior pole was 3.5 cm in diameter. We performed thymo-thymectomy by median sternotomy. Histological study revealed that the left tumor was type B2 thymoma and the other one was type A thymoma. Both were completely encapsulated without invasion, which means stage Ⅰ by Masaoka's classification. The patient has showed no evidence of recurrence for 11 years following the surgery. This is the 1st case in Japan that reported synchronous multicentric thymoma with apparently different histology of type A and B2.

[A case of Paragonimus westermani with elevated FDG uptake into a pulmonary nodular lesion and right hilar and mediastinal lymph nodes on FDG-positron-emission tomography].

A 47-year-old Chinese woman living in Japan was referred with a 2-month history of cough with hemoptysis. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed increased FDG uptake into a pulmonary nodular lesion 25 mm in greatest dimension in the right upper lobe, and right hilar and mediastinal lymph nodes. Laboratory investigation did not reveal either eosinophilia or a marked elevation of serum IgE titer. A culture of bronchial lavage fluid was sterile and culture for mycobacteria was negative. Cytological examination results of transbronchial brushing samples were Class III. A partial resection of the right upper lobe was performed because of the possibility of primary lung cancer. Pathological examination of the nodular lesion showed helminthic eggs surrounded by dense inflammatory infiltrates, which mainly consisted of lymphocytes and eosinophils. Based on the findings of a serological study for helminth, the morphological characteristics of the eggs and the patient's history of eating raw crab, the patient was given a diagnosis of Paragonimus westermani, which can mimic primary lung cancer.

Activated protein C attenuates cardiopulmonary bypass-induced acute lung injury through the regulation of neutrophil activation.

OBJECTIVE: Cardiopulmonary bypass is known to induce systemic inflammatory responses that injure multiple organs, especially the lungs. Activated protein C has been demonstrated to play an important role in the regulation of inflammation in addition to coagulation. We investigated the anti-inflammatory effects of activated protein C in a rat model of cardiopulmonary bypass. METHODS: Rats were randomized to receive an intravenous bolus of vehicle (control), 0.1 mg/kg diisopropyl fluorophosphate-activated protein C, or 0.1 mg/kg activated protein C 10 minutes before the initiation of cardiopulmonary bypass. Rats underwent cardiopulmonary bypass for 60 minutes followed by another 60-minute observation. RESULTS: The activated protein C group showed significantly higher mean arterial oxygen pressure and lower mean lung wet-to-dry weight ratio after cardiopulmonary bypass than the control and diisopropyl fluorophosphate-activated protein C groups. Furthermore, lung pathology revealed minimal inflammatory change in the activated protein C group. A marked increase in CD11b expression and a decrease in CD62L expression after cardiopulmonary bypass were observed in the control and diisopropyl fluorophosphate-activated protein C groups. However, administration of activated protein C significantly attenuated these changes. Lung content of tumor necrosis factor-α and interleukin-1ß in the activated protein C group tended to be lower than in the other groups. Lung content of macrophage inflammatory protein-2 in the activated protein C group was significantly lower than in the diisopropyl fluorophosphate-activated protein C group. CONCLUSIONS: Administration of activated protein C before cardiopulmonary bypass attenuates acute lung injury induced by cardiopulmonary bypass at least in part through the inhibition of neutrophil activation and possibly via the attenuation of proinflammatory cytokine production in this rat model of cardiopulmonary bypass.

[Interstitial pneumonitis caused by seasonal influenza vaccine].

A 74-year-old man who received seasonal influenza vaccination at a clinic developed fever and cough the following morning. He was referred to our hospital on the 5th day after vaccination because of bilateral pulmonary infiltration shadows on a chest X-ray film. Despite the administration of sulbactam/ampicillin and roxithromycin after admission, his symptoms did not improve. His bronchoalveolar lavage fluid (BALF) obtained by bronchoscopy on the 8th hospital day revealed a CD4/CD8 ratio of 6.8, 109 x 10(4)/ml, and 39% and 16% increases in lymphocyte fractions and eosinophil levels, respectively. Transbronchial lung biopsy showed organizing pneumonia. A drug-induced lymphocyte stimulation test (DLST) for seasonal influenza vaccine with BALF showed 210% of seasonal influenza (S.I). These results indicate that this vaccine caused pneumonitis with a hypersensitive reaction, according to drug-induced lung injury criteria.

Suppressive effect of phosphodiesterase type 4 inhibition on systemic inflammatory responses after cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) induces excessive production of endogenous proinflammatory mediators such as cytokines and elastase, which are responsible for the subsequent development of systemic inflammatory response syndrome (SIRS). In this study, we investigated the protective effect of rolipram against SIRS after CPB. Rats were divided into three groups (n = 5 in each): control (C), rolipram (R), and sham (S). Rats in groups C and R underwent CPB for 60 min followed by 60 min of observation, while those in group S were observed for 120 min without CPB. In group R, 40 microg/kg/min of rolipram was intravenously administered throughout the experiment. CD11b expression on neutrophils was analyzed using flow cytometry. Serum concentrations of tissue necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), macrophage inflammatory protein 2 (MIP-2), and elastase were also determined. CD11b expression at the end of the experiment was unchanged from the initial value in group R, whereas that in group C increased to almost double, and that in group S also showed a slight increase (P < 0.01). Serum TNF-alpha levels in groups R and S were lower than those observed in group C (P < 0.05). Serum IL-1beta and MIP-2 levels in groups C and R tended to be higher than those in group S, although the difference was not statistically significant. Regarding elastase, group R showed a significantly lower value than group C and a higher value than group S (P < 0.05). Phosphodiesterase type 4 inhibition seems to suppress CPB-induced SIRS through the regulation of proinflammatory mediators in this rat model.

Acute effects of direct cell implantation into the heart: a pressure-volume study to analyze cardiac function.

BACKGROUND: To safely implant cells into the myocardium, we must establish a volume that prevents compromising cardiac performance. We studied pressure-volume (PV) to investigate the adverse effects of direct cell implantation in the acute phase. METHODS: We used 21 minipigs. In the normal heart model, we studied PV by measuring various parameters (including end-systolic pressure, end-systolic elastance, dp/dtmax, end-diastolic volume, and time constant of isovolumetric left ventricular pressure fall [Tau]). We injected solutions into the left ventricular free wall (15 cm(2)). Sampling points were at baseline and after injection of saline (Group I, n = 4) or of blood (Group II, n = 4) at volumes of 1 ml and 10 ml up to 30 minutes after injection. In Group II, we injected additional blood (10 ml) 4 times. In the ischemic heart model, 1 month after ligating the left anterior descending artery, we injected 1 ml saline (Group III, n = 4), bone marrow mononuclear cells (10(8) cells/1 ml; Group IV, n = 4), or bone marrow stromal cells (10(8) cells/1 ml; Group V, n = 3). We studied PV before and after injection. RESULTS: In Group I, we found no significant changes in parameters. In Group II, end-diastolic volume after 10-ml injection (24.4 +/- 3.6 ml) was smaller than end-diastolic volume at baseline (29.5 +/- 5.8 ml, p < 0.01). Tau after 10-ml injection (39.4 +/- 5.3 msec) was greater than at baseline (35.6 +/- 4.0 msec, p < 0.01). One pig died of ventricular fibrillation after a 20-ml injection of blood. We observed no detrimental effects in Groups III, IV, and V. CONCLUSIONS: More than 10 ml cell suspension compromised diastolic function. We safely performed direct injection of bone marrow cells (1 x 10(8)/1 ml).

Bone marrow is a source of regenerated cardiomyocytes in doxorubicin-induced cardiomyopathy and granulocyte colony-stimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy.

BACKGROUND: It has been reported previously that granulocyte colony-stimulating factor (GCSF) injection improves infarcted heart function, but the mechanism remains unclear. In this study we sought to determine whether GCSF-mobilized bone marrow cells could regenerate neo-myocardium and repair doxorubicin-induced cardiomyopathy. METHODS: C57BL/6 mice were irradiated and bone marrow cells (BMC; 1 x 10(6)) from green fluorescent protein (GFP) mice (GFP-BMC) were transplanted intravenously, followed by splenectomy. Doxorubicin (2.5 mg/kg, 6 times for 2 weeks) was administered intraperitoneally 2 weeks later. GCSF (50 microg/kg/day for 8 days) was administered sub-cutaneously after doxorubicin injection (Group I, n = 11) and 3 weeks later (Group II, n = 8), and saline was injected in Group III animals (n = 8). Eight weeks after doxorubicin injection, the excised hearts were studied immunologically and electron microscopically. RESULTS: Survival rates were 81.8% in Group I, 50.0% in Group II and 62.5% in Group III. The number of GFP-BMC in Group I (15.4 +/- 7.4 per high-power field) was highest (p < 0.05). In all groups, cardiac troponin I-positive cells derived from GFP-BMC were observed in the hearts. GFP-BMC in hearts stained positively against cardiac troponin I (4.3 +/- 2.5%), myosin heavy chain (5.0 +/- 4.3%), atrial natriuretic peptide (ANP; 3.9 +/- 2.4%) and connexin 43 (11.9 +/- 7.3%) in Group I. Myofibrils, mitochondria and fundamental architecture were almost all preserved in Group I, whereas hearts were severely damaged in Groups II and III. CONCLUSIONS: Bone marrow was shown to be one of the sources of regenerated cardiomyocytes in the doxorubicin-induced cardiomyopathic heart. Early administration of GCSF enhanced the migration of bone marrow cells into the heart, and attenuated the cardiotoxicity of doxorubicin.

Phosphodiesterase type 4 inhibitor prevents acute lung injury induced by cardiopulmonary bypass in a rat model.

OBJECTIVES: Cardiopulmonary bypass (CPB) induces systemic inflammatory response with neutrophil activation and subsequent lung dysfunction. Rolipram, a selective phosphodiesterase type 4 inhibitor, blocks the decrease in levels of cyclic adenosine monophosphate associated with neutrophil activation. Here, we tested the protective effect of rolipram on CPB-induced lung injury in the rat. METHODS: Rats were divided into three groups: control (C), rolipram (R) and sham (S). In the C and R groups, animals underwent CPB at a flow rate of 60 ml/kg per min for 60 min followed by another 60-min observation, whereas the S group rats were sustained for 120 min only with median sternotomy and the placement of cannulae for CPB. Rolipram (40 microg/kg per min) was administered to the R group rats by continuous intravenous infusion from 10 min before the establishment of CPB to the end of the experiment. RESULTS: The R and S groups showed significantly higher mean arterial oxygen pressure and lower mean lung wet-to-dry weight ratio compared with those observed in the C group (R: 489+/-44 or S: 527+/-55 vs. C: 287+/-185, and R: 5.0+/-0.4 or S: 4.7+/-0.3 vs. C: 5.9+/-0.5, respectively; (P < 0.01). Although CD11b expression levels on circulating neutrophils in the C group doubled after CPB, those in the R and S groups remained almost the same (P = 0.0008). Intrapulmonary tumor necrosis factor-alpha concentrations (pg/microg protein) in the C group tended to be higher than those observed in the R and S groups (R: 5.2+/-2.1, S: 5.0+/-2.1 and C: 8.9+/-5.4; R vs. C: P = 0.09 and S vs. C: P = 0.08). Pathological study of lungs revealed that more alveolar hemorrhage and neutrophil accumulation were observed in the C group compared to the R and S groups. CONCLUSIONS: These results suggest that rolipram prevents acute lung injury via the inhibition of neutrophil activation during and after CPB in this setting of a rat model.

Bone marrow mononuclear cell transplantation had beneficial effects on doxorubicin-induced cardiomyopathy.

BACKGROUND: Cell transplantation is a promising therapy for treating end-stage heart failure. Bone marrow mononuclear cells (BMMNC) have been used to enhance angiogenesis in ischemic heart disease. However, the effect of BMMNC transplantation in non-ischemic dilated cardiomyopathy is unknown. In this study, we evaluated the efficacy of BMMNC transplantation in doxorubicin-induced cardiomyopathy in a rat model. METHODS: Doxorubicin (15 mg/kg, IP) was introduced into 52 Lewis rats. They were divided into 3 groups at 4 weeks after injection: transplant group (TX, BMMNC [1 x 10(6)] implantation, n = 18), control group (CN, saline injection, n = 18), and sham group (SH, thoracotomy, n = 16). At 4 weeks after surgery, we used echocardiography to measure systolic left ventricular diameter (LVDs), diastolic left ventricular diameter (LVDd), fractional shortening (FS), and left ventricular wall thickness/LVDs. We used a Langendorff apparatus to measure systolic, diastolic, and developed pressures. We used radioimmunoassay to measure circulating atrial natriuretic peptide concentration, and we performed histologic study, including electron-microscopic study. RESULTS: Left ventricular wall thickness/LVDs in the TX group was the largest of all groups (p < 0.05). Systolic and developed pressures in the TX group were the greatest (p < 0.005). Systolic left ventricular diameter, FS, and end-diastolic pressure in the TX group were smaller than in the SH group (p < 0.05). These cardiac parameters did not differ significantly between TX and CN groups, but secondary changes (decreased heart weight, developed ascites, and increased atrial natriuretic peptide concentration) caused by doxorubicin-induced heart failure were most attenuated in the TX group. In the TX group, vascular density was greatest (p < 0.05) in the left ventricular free wall and in the septum. In addition, electron microscopy showed that myocardium in the TX group was most maintained. CONCLUSION: Bone marrow mononuclear cell transplantation had beneficial effects in doxorubicin-induced cardiomyopathy.

Interleukin 10 gene transfection of donor lungs ameliorates posttransplant cell death by a switch from cellular necrosis to apoptosis.

BACKGROUND: We have previously shown that cell death is a pathophysiologic consequence of ischemia-reperfusion and that interleukin-10 gene therapy improves the function of transplanted lungs. Interleukin-10 downregulates the inflammatory response and can inhibit apoptosis. The objective was to determine whether donor lung transfection with the interleukin-10 gene ameliorates lung dysfunction by decreasing cell death after transplantation. METHODS: Single lung transplants were performed in 3 groups of rats (n = 5 each): AdhIL-10, transtracheal administration of Ad5E1RSVhIL-10 (5 x 10(9) pfu); EV, empty vector; and VD, vector diluent (3% sucrose). After in vivo transfection, donor lungs were excised, stored at 4 degrees C for 24 hours, and then transplanted. After 2 hours of reperfusion, lungs were flushed with trypan blue and fixed. TUNEL staining was used for the detection of apoptosis. This combined staining technique allows one to determine the mode of cell death by distinguishing apoptotic dead cells from necrotic dead cells. RESULTS: Lung function was superior in the interleukin-10 group (P =.0001) vs the EV and VD group (Pao(2): 240 +/- 31 mm Hg vs 98 +/- 17 mm Hg vs 129 +/- 11 mm Hg, respectively). Although the total number of dead cells (as percent of total cells) was similar in all groups (32.7% +/- 3.2%, 30.2% +/- 2.5%, and 30.3% +/- 3.8%), interestingly, apoptosis was highest in interleukin-10 lungs (9.7 +/- 1.9 vs 2 +/- 1.9 and 1.8 +/- 2, P =.0001), and necrosis was lowest in the interleukin-10 group (20.6 +/- 5.7 vs 28.3 +/- 3.1 and 30.3 +/- 4.2, P =.01). CONCLUSIONS: AdhIL-10 gene transfection improves function of transplanted lungs. Although the total number of cells dying as a result of the transplant process did not change, the mode of cell death appears to have been modified. It is possible that AdhIL-10, by decreasing proinflammatory cytokine production, ameliorates the overall injury and preserves the ability of damaged cells to undergo a more quiescent and less tissue-damaging mode of cell death-apoptosis, rather than necrosis.

[Impact of cimetidine on growth and metastasis of surgically transplanted Lewis lung cancer].

PURPOSE: Histamine has multiple biological functions and its immunomodulatory actions are not fully understood. In the current study, we investigated the effect of cimetidine, which is a histamine-2 receptor antagonist, on the progress of transplanted Lewis lung cancers using a mouse model. METHODS: A piece of Lewis lung cancer weighing 15 mg was transplanted into the subcutaneous space on the back of each C 57 BL/6 mouse. Mice were randomized into a no-treatment control group (CO) or one of two treatment groups. In the treatment groups, 16 mg/kg/day (LD) or 160 mg/kg/day (HD) of cimetidine was orally administered from one week before the day of transplantation to the time of sacrifice. Subcutaneous tumors and lungs were excised on the 28th or 42nd postoperative day. RESULTS: The mean vascular densities of the subcutaneous tumors on day 28 were 55.7 +/- 23.9/mm2 in CO, 88.0 +/- 16.3/mm2 in LD and 122.6 +/- 16.9/mm2 in HD (p < 0.05; CO vs. LD or HD, LD vs. HD). On day 42, mean weights of the subcutaneous tumors and the numbers of metastatic lung tumors were 6.0 +/- 2.1 g in CO, 7.9 +/- 1.2 g in LD and 10.0 +/- 1.9 g in HD (p < 0.05; CO vs. HD), and 7.5 +/- 6.0 in CO, 17.0 +/- 3.0 in LD and 19.8 +/- 7.4 in HD (p < 0.05; CO vs. HD), respectively. CONCLUSIONS: These results suggest that cimetidine dose-dependently enhances the angiogenesis, growth and metastasis of surgically transplanted Lewis lung cancer in a mouse model of this type.

Transplant immunosuppression enhances efficiency of adenoviral-mediated gene retransfection: inhibition of interferon-gamma and immunoglobin G.

BACKGROUND: Transplant immunosuppression regimen facilitates successful adenovirus-mediated gene transfection and retransfection in the rat lung. Herein, we investigated the effect of this strategy on circulating cytokines and antiadenoviral immunoglobin G antibody. METHODS: Male Lewis rats were transfected with 1 x 10(9) pfu/mL of E1-deleted Ad5CMVLacZ vector transtracheally. Rats were randomly assigned to receive daily intraperitoneal triple immunosuppression regimen consisting of cyclosporine (15 mg/kg per day), azathioprine (6 mg/kg per day), and methylprednisolone (2.5 mg/kg per day), or normal saline solution. Retransfection was performed 35 days later to all nonimmunosuppressed animals, whereas immunosuppressed rats were further randomized to receive retransfection or phosphate-buffered saline. Animals were sacrificed on days 1, 2, 7, 35, 42, and 49 after the initial transfection. Beta-galactosidase activity was measured on lung homogenates. Interferon-gamma, tumor necrosis factor-alpha, and antiadenoviral immunoglobin G were measured from the serum. RESULTS: Enhanced and prolonged transgene expression was observed in immunosuppressed animals, especially after retransfection. Concentrations of serum tumor necrosis factor-alpha in both groups were less than 12 pg/mL throughout the study. A significant increase in serum interferon-gamma levels was observed in nonimmunosuppressed animals after retransfection; this was not seen in the immunosuppressed animals. Serum antiadenoviral immunoglobin G titers in both groups were sharply elevated on day 1, and declined to basal levels by day 7, reflecting a preexisting level of humoral immunity to adenovirus. The titer in nonimmunosuppressed rats was significantly increased after retransfection, but remained at very low level in immunosuppressed animals. CONCLUSIONS: Inhibition of interferon-gamma and antiadenoviral immunoglobin G production by triple immunosuppressants may be part of the mechanisms that lead to enhanced and prolonged transgene expression after retransfection.

Soluble transforming growth factor-beta type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of Bronchiolitis obliterans.

Post-transplant bronchiolitis obliterans (BO) is characterized by fibroproliferation and fibrous obliteration of distal airways in chronically rejected lungs. In this study, using a rat heterotopic allogeneic tracheal transplant model of BO, we evaluated the expression of transforming growth factor-beta (TGFbeta) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGFbeta staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGFbeta receptor type III (TGFBIIIR), by blocking TGFbeta binding to its membrane receptors, functions as a TGFbeta antagonist. To study the role of TGFbeta in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 x 10(9) particles) was performed topically at the site of transplant on Day 5 after transplantation, which leads to inhibition of fibrous airway obliteration. In contrast, empty vector gene delivered through intramuscular injection, or given locally at Days 0 or 10 after tracheal transplantation had no significant effect. These results suggest that TGFbeta expressed in the allografts plays a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGFbeta activity locally. Adenoviral-mediated soluble TGFBIIIR gene transfection should be further explored as a potential therapeutic modality for BO and other conditions involving chronic fibrosis.