Treatment Of Bronchiolitis Obliterans Research Articles

Expert consensus on the diagnosis and treatment of bronchiolitis obliterans in children (2023)

Expert consensus on the diagnosis and treatment of bronchiolitis obliterans in children (2023)

Worldwide Bronchiolitis obliterans research: A bibliometric analysis of the published literature between 2002 and 2022.

Bronchiolitis obliterans (BO) is a rare and irreversible chronic respiratory disease. The diagnosis of BO is challenging, and there still needs to be specific therapies and uniform treatment guidelines available. Research on BO has grown steadily over the past 20 years, and with the continued interest of researchers in this area, a bibliometric study of BO becomes necessary. This topic aims to assess the current state of research in BO over the last 2 decades and to identify research hotspots and emerging directions. Information on BO-related articles were obtained from the Science Citation Index Expand of the Web of Science Core Collection (WOSCC [SCI-E]) database. Citespace (6.1.R6), VOSviewer (1.6.18), and the online bibliometrics website (https://bibliometric.com/) were used for bibliometric analysis mainly to include country/region, institution, author, journal, keywords, and references and to construct visual knowledge network diagrams. A total of 4153 publications from the WOSCC [SCI-E] database were included in this study. Most publications come from the United States, Japan, and Germany, which collaborate relatively more frequently. Research institutions in the United States, especially the University of Washington, published the largest number of BO-related articles. Regarding authors, Vos, R is the most productive author, while Verleden, GM is the most influential in BO. In addition, JOURNAL OF HEART AND LUNG TRANSPLANTATION is the journal with the most published articles. The most cited article is Estenne M, 2002. Based on the clustering analysis of keywords and references, the diagnosis of bronchiolitis obliterans syndrome (BOS), treatment of BOS, and risk factors of BO are the current research hotspots and future research trends. We analyzed the publication trends in BO by bibliometrics and mapped the knowledge network of major contributing countries/regions, institutions, authors, and journals. Current research hotspots were found based on the main keywords and references. The outcome may help researchers identify potential collaborators, collaborating institutions, and hot fronts in BO to enhance collaboration on critical issues and improve the diagnosis and treatment of BO.

Clinical observation on the safety and efficacy of umbilical cord mesenchymal stem cells in the treatment of bronchiolitis obliterans after allogeneic haematopoietic stem cell transplantation

ABSTRACT Graft-versus-host disease (GVHD) is caused by a pathologic and destructive response of the organism as a result of the interaction between donor immunocompetent T lymphocytes and the recipient tisular antigens1. Graft-versus-host disease is considered a serious complication of hematopoietic stem cell transplantation. The skin, oral cavity and lungs are commonly affected organs. Among these complications bronchiolitis obliterans syndrome is a serious complication, which even can be life-threatening. Therefore, this research aims to do a clinical observation on the safety and efficacy of umbilical cord mesenchymal stem cells in the treatment of bronchiolitis obliterans after allogeneic haematopoietic stem cell transplantation. Fifteen patients were included in this study, who received allogeneic hematopoietic stem cell transplantation. Among these patients, both of them were treated with azithromycin, montelukast, glucocorticoid and pirfenidone. Two of them did not receive second line anti-rejection treatment due to economic reasons, and three of them were treated with mesenchymal stem cells. These bronchiolitis obliterans syndrome-related symptoms such as shortness of breath, chest tightness and wheezing have improved. Two of them died due to bronchiolitis obliterans syndrome related complications such as respiratory failure. Two of them not only improve the symptoms but also increased the FEV1/FVC, who were treated with mesenchymal stem cells. The comprehensive treatment regimen containing imatinib and ruxolitinib is safe and effective and mesenchymal stem cell is a promising treatment option to improve the prognosis of post-HSCT BOS.

Artificial Intelligence Algorithm-Based High-Resolution Computed Tomography Image in the Treatment of Children with Bronchiolitis Obliterans by Traditional Chinese Medicine Method of Resolving Phlegm and Removing Blood Stasis.

This research was aimed to explore the application of high-resolution computed tomography (HRCT) based on intelligent iterative reconstruction technique in the early diagnosis and treatment of bronchiolitis obliterans (BO) in children and to explore the efficacy of traditional Chinese medicine (TCM) in resolving phlegm and removing blood stasis. Sixty pediatric patients with BO were selected as the study subjects and diagnosed by HRCT scanning, and the scanned images were processed by iterative reconstruction technique. The patients were treated with TCM therapy of resolving phlegm and removing blood stasis alone (group A), HRCT-guided TCM therapy of resolving phlegm and removing blood stasis (group B), and iterative reconstruction HRCT-guided TCM therapy of resolving phlegm and removing blood stasis (group C). The results showed that the lung HRCT image after iterative reconstruction was closer to the original image than that after filtered back projection reconstruction, and the edge of the image after filtered back projection reconstruction was more blurred and the noise was higher. The image obtained by iterative reconstruction technique was smoother and clearer, and the image stability after iterative reconstruction was higher. The treatment results showed that the proportion of moderate and severe obstruction in group C was 5.18%, which was significantly lower than that in group A (18.75%) and group B (11.29%), and group B was significantly lower than that in group A (18.75%) (P < 0.05). The proportion of clinical effect in group C after treatment was 70.18%, significantly higher than that in group A (55.5%) and group B (63.34%), and that in group B was significantly higher than that in group A (55.5%) (P < 0.05). In summary, the lung HRCT after iterative reconstruction can more clearly and intuitively show the lesion site, which has a key role in guiding the early diagnosis and treatment planning of BO; the HRCT image based on iterative reconstruction technique combined with TCM treatment of removing blood stasis and resolving phlegm has a better therapeutic effect on children, with a high application value.

Interleukin-18: A Novel Participant in the Occurrence, Development, and Drug Therapy of Obliterative Bronchiolitis Postlung Transplantation.

Background Obliterative bronchiolitis (OB) was a main cause of deterioration of long-term prognosis in lung transplant recipients after the first posttransplant year. Proinflammatory cytokine interleukin-18 (IL-18) strengthened both the natural immunity and acquired immunity and played an important role in organ transplantation. The roles of IL-18 in the occurrence, development, and drug treatment of OB remained unclear. Methods Small interfering RNA (siRNA) against mouse IL-18 (siRNA-IL-18) was used to silence IL-18 expression. Mouse heterotopic tracheal transplantation model was used to simulate OB. Recipient mice were divided into 5 groups (n = 12) according to donor mouse strains and drug treatment: isograft group, allograft group, allograft+tacrolimus group, allograft+azithromycin group, and allograft+tacrolimus+azithromycin group. The luminal obliteration rates were pathological evaluation. Expressions of cytokines and MMPs were detected by real-time PCR, western blot, and enzyme chain immunosorbent assay (ELISA). Results The luminal obliteration rates of IL-18 of the siRNA-IL-18 group were significantly lower than those of the negative control group (p < 0.0001) and the blank control group (p = 0.0002). mRNA expressions of IFN-γ, EMMPRIN, MMP-8, and MMP-9 of the siRNA-IL-18 group were significantly lower than those of the negative and blank control groups. No tracheal occlusion occurred in grafts of the isograft group. The rates of tracheal occlusion of the allograft group, allograft+tacrolimus group, allograft+azithromycin group, and allograft+tacrolimus+azithromycin group were 72.17 ± 4.66%, 40.33 ± 3.00%, 38.50 ± 2.08%, and 23.33 ± 3.24%, respectively. There were significant differences between the 4 groups (p < 0.001). Serum protein expressions of IL-17 (p = 0.0017), IL-18 (p = 0.0036), IFN-γ (p = 0.0102), and MMP-9 (p = 0.0194) were significantly decreased in the allograft+tacrolimus+azithromycin group compared to the allograft group. Conclusions IL-18 could be a novel molecular involved in the occurrence, development, and drug treatment of OB.

Case Report of Paraneoplastic Pemphigus-Related Bronchiolitis Obliterans in a Follicular Lymphoma Patient undergoing a CHOP with Azathioprine Regimen

Paraneoplastic pemphigus (PNP) is a rare, lethal, paraneoplastic autoimmune mucocutaneous blistering disease commonly associated with lymphoproliferative disorders including malignant lymphomas. Lymphoproliferative disorders associated with PNP are sometimes associated with serious lung complications such as bronchiolitis obliterans (BO). Because of its rarity, guidelines have not been established for management of PNP. Furthermore, most patients die within 1 year. We report treatment of lymphomaassociated PNP and BO using CHOP chemotherapy with azathioprine. A 57-year-old Thai woman suffered from systemic blisters, severe erosive stomatitis, and abdominal distension. Computed tomography revealed multiple lymphadenopathies. She was diagnosed with follicular lymphoma grade 1 (Ann Arbor stage IVA) and PNP-related BO. The patient underwent four cycles of CHOP and azathioprine. The erosive stomatitis and systemic blisters resolved completely. The lymph nodes became smaller with a partial response of the underlying follicular lymphoma. However, the bronchiolitis obliterans persisted. The patient achieved 15 months of survival. The present case suggests that intensive chemotherapy with immunosuppressive improves the prognosis of patients with PNP-related BO associated with lymphoma. Keywords: Follicular lymphoma, Paraneoplastic pemphigus, Bronchiolitis obliterans

Imatinib melylate as second-line treatment of bronchiolitis obliterans after allogenic hematopoietic stem cell transplantation in children.

The onset of bronchiolitis obliterans (BO) as a pulmonary manifestation of chronic graft vs host disease dramatically changes the prognosis of children undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the overall survival (OS) of children with BO treated with imatinib mesylate (IM). This study included children who underwent allo-HSCTs between January 2000 and December 2016. Among 345 patients who underwent HSCTs, 293 were evaluable for BO and 26 (8.9%) developed BO. The cumulative incidence of BO was 4.8% (95% confidence interval [CI], 2.8-7.5) at 1 year and 7.7% (95% CI, 5.1-11.1) at 3 years after transplantation. In the group of HSCTs (n = 67) complicated by chronic GvHD (c-GVHD), the incidence rate of BO was 38.8%. In total, 96.1% of patients with BO had c-GvHD worse thanmoderate grade, which was present in 70.7% of patients without BO (P = .011). The mortality rates were 46.1% in the BO group and 27.4% in the group without BO. Half of the patients with BO (n = 13) received IM, and the overall response rate was 76.9%. Four years after HSCT, OS was 42.6% (95% CI, 18.2-65.3) in the group without IM and 83.3% (95% CI, 27.3-97.5) in the group with IM. BO after HSCT in the pediatric population has a high incidence and mortality rate. In terms of overall response and tolerability, this study showed relevant improvements in the prognosis of children with BO after the introduction of IM. Further prospective studies among children are needed to confirm these results.

Relapse Rates in Patients Receiving Azithromycin for the Treatment of Bronchiolitis Obliterans after Allogeneic Hematopoietic Stem Cell Transplant

Introduction The FDA issued a warning on the increased risk of hematologic relapse based on the ALLOZITHRO trial, recommending azithromycin not be used long-term in patients that have undergone allogenic hematopoietic stem cell transplant (HSCT). In the ALLOZITHRO trial, azithromycin was started at the time of the conditioning regimen for prophylaxis of bronchiolitis obliterans (BO); however, at our site and many others across the country, azithromycin is initiated after BO. Objective The goal of this study was to evaluate if azithromycin used in treatment of BO is associated with an increase in the rate of relapse. Methods IRB approval was obtained prior to review of the electronic medical record and the Mayo Clinic HSCT database. Adult patients who received an allogeneic HSCT from January 2008 – August 2018 for a malignant disease and received ≥ 2 weeks of azithromycin were included in this study. Patients were excluded if they received Results Of 466 adult patients who received an allogenic HSCT at Mayo Clinic Hospital-Rochester for malignant disease, 185 patients received azithromycin. Of 185 patients who received azithromycin, 87 were excluded: declined research participation (n = 7), received Conclusion The use of azithromycin as treatment for BO was not associated with a high incidence of disease relapse in this study. Further research is needed to confirm our findings.

Post-infectious bronchiolitis obliterans.

Bronchiolitis obliterans is a rare and severe chronic lung disease resulting from a lower respiratory tract lesion. It may occur after a bone marrow or lung transplantation, infectious diseases, or less frequently after inhaling toxic substances or after connective tissue diseases. Pathology, pathogenesis, and molecular biology, as well as the best treatment of bronchiolitis obliterans, remain the subject of ongoing research. This review discusses our current knowledge of different areas of bronchiolitis obliterans associated with infectious lesions.

Treatment of bronchiolitis obliterans in children

The incidence of Bronchiolitis Obliterans(BO) is on the rise in the recent years.There is no unified treatment method at present, glucocorticoid, antibiotics and aerosol inhalation therapy are commonly used clinically.Bronchial alveolar lavage, as a new technique for treatment of children BO, is of great value to the study of prediction, diagnosis and pathogenesis of children BO.The current status of clinical treatment of children BO will be summarized in this paper. Key words: Bronchiolitis obliterans; Treatment; Bronchoalveolar lavage; Glucocorticoid

LTB4 and montelukast in transplantation-related bronchiolitis obliterans in rats

BackgroundLung transplantation is the only effective treatment for end-stage lung diseases. Bronchiolitis obliterans, which is known as non-infectious chronic lung allograft dysfunction (CLAD) in the new classification, is the greatest threat to long-term survival after lung transplantation. This study investigated the role of leukotriene B4 (LTB4) and montelukast in transplantation-related bronchiolitis obliterans and discussed the pathophysiological significance of LTB4 in chronic rejection.MethodsRats were randomly divided into an experimental group (montelukast), a positive control group (dexamethasone), and a blank control group (normal saline solution; NS). Each piece of trachea removed from a F344 rat was transplanted into a Lewis rat through a 5-mm incision at the episternum by subcutaneous embedding. The recipients were treated with gastric lavage with 3 mg/kg · d montelukast suspension, 1 mg/kg · d dexamethasone, and 1 mL/kg · d NS, respectively, in each group. On Day 28, peripheral blood was drawn to measure the white blood cell counts and plasma LTB4 levels. The donor specimens were stained by H-E and Masson, and their organizational structure and extent of fibrosis were visually assessed. The measurement data were compared using one-way analysis of variance, and the categorical data were compared using the chi-square test. A P value of less than 0.05 was considered to indicate statistical significance.ResultsThe white blood cell counts of the montelukast, dexamethasone, and NS groups were (16.0 ± 4.2) × 109/L, (19.5 ± 11.6) × 109/L, and (25.8 ± 3.6) × 109/L; no statistical significance was found (P = 0.101). The concentrations of LTB4 were 2230 ± 592 pg/mL, 1961 ± 922 pg/mL, and 3764 ± 1169 pg/mL, and statistical significance was found between the NS group and each of the others (P = 0.009). The percentages of tracheal occlusion were 73.6% ± 13.8%, 23.4% ± 3.2%, and 89.9% ± 11.3%, and statistical significance was found among the three groups (P = 0.000).ConclusionsThe study established a model to simulate bronchiolitis obliterans after clinical lung transplantation. Oral administration of montelukast reduced plasma LTB4 levels in rats and played a preventive role against tracheal fibrosis after transplantation. This suggests that LTB4 may be involved in bronchiolitis obliterans after pulmonary transplantation. This study indicates a new direction for research into the prevention and treatment of bronchiolitis obliterans after lung transplantation.

Azithromycin for the Treatment of Obliterative Bronchiolitis after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Obliterative bronchiolitis (OB) is a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Our objective was to perform a systematic review and meta-analysis of the impact of azithromycin on change in forced expiratory volume in 1 second (FEV1). We searched MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL and Scopus databases and included studies that compared azithromycin with placebo or no intervention in the treatment of OB or bronchiolitis obliterans syndrome (BOS) in patients who had undergone allogeneic HSCT. Ninety-one unique publications were identified, and 4 studies met inclusion criteria, with a total of 90 patients. Changes in FEV1 were measured between 12 and 24 weeks after initiation of treatment. The meta-analysis demonstrated a mean increase in FEV1 of 30 mL (95% confidence interval, −260 to +330 mL; P = .82) after initiation of azithromycin. One patient death was reported but not attributed to azithromycin therapy. In conclusion, current evidence can neither support nor refute the use of azithromycin in the treatment of patients who develop OB/BOS after HSCT. Further studies are needed to determine whether azithromycin is beneficial for the treatment of OB/BOS in this setting.

Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation

Imatinib, a tyrosine kinase inhibitor, has been proposed as a potential anti-fibrotic agent for fibroproliferative diseases, including bronchiolitis obliterans (BO). However, the underlying anti-fibrotic mechanisms of the agent remain unclear. We evaluated whether bone (BM)-derived progenitor cells, fibrocytes, might be a target of imatinib in the attenuation of BO. We used a murine BO model induced by heterotopic tracheal transplantation and assessed the origin of fibroblasts by using green fluorescent protein-BM chimeric mice. We also evaluated the effects of imatinib on luminal obstruction and fibrocyte accumulation. The effects of imatinib on fibrocyte migration and differentiation were assessed by culturing fibrocytes in vitro. In the murine BO model, tracheal allografts showed epithelial injury and developed complete luminal occlusion 28 days after transplantation. Most of the mesenchymal cells that had accumulated in the tracheal allograft were derived from BM cells. Imatinib treatment ameliorated the airway luminal occlusion and significantly reduced the number of fibrocytes in the allografts. In vitro studies showed that imatinib inhibited migration of cultured blood fibrocytes via the platelet-derived growth factor/platelet-derived growth factor receptor axis. Imatinib also inhibited differentiation of fibrocytes via suppression of c-Abl activity that was essential for the differentiation of monocytes to fibrocytes. Imatinib prevents airway luminal obstruction by inhibiting the migration and differentiation of fibrocytes. Fibrocytes may be a novel target in the prevention and treatment of BO.

Cell therapy in the treatment of bronchiolitis obliterans in a murine model.

To evaluate the importance of stem cells derived from adipose tissue in reducing graft inflammation in a murine model of allogeneic heterotopic tracheal transplant. We performed a heterotopic tracheal allografting in dorsal subcutaneous pouch and systemically injected 5x105 mesenchymal stem cells derived from adipose tissue. The animals were divided into two groups according to the time of sacrifice: T7 and T21. We also carried out histological analysis and digital morphometry. The T7 animals treated with cell therapy had median obstructed graft area of 0 versus 0.54 of controls (p = 0.635). The treated T21 subjects had median obstructed graft area of 0.25 versus 0 in controls (p = 0.041). The systemically injected cell therapy in experimental murine model of bronchiolitis obliterans did not reduce the severity of the allograft inflammation in a statistically significant way in seven days; Conversely, in 21 days, it increased the allograft inflammatory process.

254. Hepatocyte Growth Factor Gene Modification Enhances the Inflammation-Alleviating Effect of Umbilical Cord Derived Mesenchymal Stem Cells in a Bronchiolitis Obliterans Model

BACKGROUNDS: Bronchiolitis obliterans is a serious, steadily, noninfectious, and fatal pulmonary complication. Currently specific and effective therapeutics for prevention or reversal of bronchiolitis obliterans is lacking. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF) gene modified mesenchymal stem cells (MSCs) on bronchiolitis obliterans.METHODS: A mouse model of experimental bronchiolitis obliterans was established by subcutaneously transplanting the tracheas from C57BL/6 mice into Balb/C recipients. These model mice were administered saline, Ad-HGF-modified human umbilical cord-MSCs (MSCs-HGF) or Ad-Null-modified MSCs (MSCs-Null). The distribution of the transplanted cells was detected by using real-time PCR (rt-PCR). The therapeutic effects of MSCs-Null and MSCs-HGF were evaluated by using FACS for lymphocyte immunophenotype of spleen, ELISA and rt-PCR for cytokine expression, and histopathological analysis for the transplanted trachea.RESULTS: The administrated MSCs mainly distributed in the transplanted trachea, blood, liver and lung of the recipients; HGF gene modification could enhance the engraftment of MSCs. The histopathological recovery of allografts tracheas was improved significantly after MSCs-Null and MSCs-HGF treatment and the beneficial effects were particularly observed in MSCs-HGFtreated mice. Furthermore, the allo-transplantation induced immunophenotype disorders of the spleen cells, including Treg, Th1, Th2 and Th17 cells, were attenuated in both cell treated groups. MSCs-HGF treatment reduced expression and secretion of inflammation cytokines interferon-gamma and increased expression of anti-inflammatory cytokine IL-4 and IL-10. It also decreased the expression level of the profibrosis factor transforming growth factor-beta.b.CONCLUSIONS: Treatment of bronchiolitis obliterans with HGF gene modified MSCs results in reduction of local inflammation and promotion in recovery of allografts tracheas histopathology in a mouse model. These findings might provide an effective therapeutic strategy for bronchiolitis obliterans.

MicroRNA screening and functional study of obliterative bronchiolitis in a rat model simulating lung transplantation.

The aim of this study was to provide the experimental basis for effective prevention and treatment of obliterative bronchiolitis (OB) by studying the changes on the microRNA (miRNA) expression profile after an orthotopic tracheal transplantation (OTT) simulating lung transplantation (LT). The OTT was performed on inbred rats to establish an OB animal model simulating LT, which was confirmed successful through pathological examination after 4 weeks. A miRNA microarray was used to screen for the most significantly differentially expressed miRNA in the OB tissues of donor transplanted trachea and real-time quantitative PCR was then used to validate the reliability of the microarray results. The microarray detection obtained 29 OB-related miRNAs, composed of 15 and 14 significantly up- and down-regulated miRNAs, respectively, among which miR-146a, miR-155, and miR-451, whose function is involved in the immune and inflammatory reactions, were subjected to relative quantitation research. The LT-simulated OTT-induced OB showed significantly differential expressions of multiple miRNAs, among which miR-146a and miR-155 were highly expressed, while miR-451 was lowly expressed, suggesting that these miRNAs may play an important regulatory role in the OB pathological process after LT.

Bronchiolitis obliterans with allogeneic hematopoietic cell transplantation: a 10-year experience of the Okayama BMT Group

Bronchiolitis obliterans (BO) is a devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively studied 465 patients who underwent HSCT in the Okayama BMT Group between 2000 and 2009, and describe the detailed clinical features of 13 patients with BO. The 5-year cumulative incidence of BO was 3.43 %. The median time from transplantation to onset of BO was 15 months. In seven of the 13 patients, the primary symptom was only cough, indicating that cough was an important initial symptom for early diagnosis. The median duration from the onset of BO to the requirement of O2 supplementation was 13 months and the main cause of death was respiratory failure. History of chronic graft-versus-host disease was a significant risk factor. Furthermore, female recipients were at greater risk of BO than male recipients; however, no other previously reported risk factors were detected. It is currently difficult to prevent BO on the basis of the reported risk factors. A novel strategy for the early diagnosis and treatment of BO is required.

Bilateral lung transplantation for bronchiolitis obliterans after allogeneic bone marrow transplantation: a case report and literature review

To explore the feasibility and efficiency of lung transplantation in the treatment of bronchiolitis obliterans (BO) after allogeneic bone marrow transplantation (allo-BMT). We reported one case of bilateral lung transplantation for BO after allo-BMT and reviewed the related literatures. A 23 year-old man diagnosed as BO after allo-BMT underwent a sequential bilateral lung transplantation through bilateral anterolateral thoracotomy without sternal division. The patient suffered from acute rejection on post-operation day (POD) 2, and cured by mechanical ventilation, large dose of methylprednisolone and gamma globulin. The patient was transferred out of the intensive care unit on POD 14 and discharged from the hospital on POD 43. Chest CT scans and pulmonary function tests showed good performance in 3 and 6 months follow-up period. BO is one of the late common non-infectious pulmonary complication after allo-BMT. For patients who have no response to medication, lung transplantation is the only efficient treatment choice so far, which can prolong survival and improve the quality of life. However, limited by small samples, optimal surgery time and appropriate care of postoperative complications still need accumulation of experience by multicenter and large samples studies.

Overexpression of IL-1 Receptor Antagonist Attenuates Obliterative Bronchiolitis in Murine Tracheal Transplant Model

Purpose Obliterative bronchiolitis (OB) remains an impediment to long-term survival after lung transplantation. IL-1 beta (IL-1β) has been studied as proinflammatory and profibrotic factor in allograft chronic lung tissue rejection. IL-1 receptor antagonist (IL-1rn) is competitive inhibitor to IL-1β and mediates the anti-inflammatory and antifibrotic effects of mesenchymal stem cells during lung injury. We hypothesized that IL-1rn overexpression prevents the progression of OB in an established heterotopic tracheal transplantation model. Methods and Materials Tracheas from BALB/c mice were implanted and wrapped in the omentum of BALB/c (isografts), C57BL/6 (allografts), IL-1rn overexpression (IL-1rn+/+), IL-1rn knock out (IL-1rn-/-) mice. The tracheas explanted after 21 days were evaluated histologically, and real time-PCR for IL-1rn, IL-1β, IL-1 alpha (IL-1α) mRNA levels. Cytokine quantification for these proteins in plasma samples was done by ELISA 21 days after surgery. Results IL-1rn overexpression mice showed significant reduction of the tracheal luminal occlusion compared to control allograft animals (p figure 1 ] There was also significant increase in plasma IL-1rn levels in the IL-1rn +/+ animals as compared to other groups (p Conclusions The results suggest that IL-1rn overexpression protects against experimental OB. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new strategy for the treatment of OB.

Mesenchymal stem cells reprogram host macrophages to attenuate obliterative bronchiolitis in murine orthotopic tracheal transplantation

After lung transplantation, obliterative bronchiolitis (OB) is one of the major limitations for the long-term survival of allografts. At present, effective treatment to prevent this phenomenon remains elusive. Mesenchymal stem cells (MSCs) are capable of modulating the immune system through the interaction with a wide range of immune cells. Here, we found that treatment of mice with bone marrow derived MSCs prevents the development of airway occlusion and increased IL-10 levels in trachea grafts, which was eliminated by the depletion of macrophages. Mechanistically, MSCs-derived PGE2, through the receptors EP2 and EP4, promoted the release of IL-10 and inhibited the production of IL-6 and TNF-α by macrophages. These results suggest that MSCs can both decrease the innate inflammatory responses and prevent allograft rejection by down-regulating the levels of IL-6 and TNF-α and increasing IL-10 production respectively. For easy availability and immune privilege, MSC-based treatment of OB provides an effective strategy for regulation of immune responses in lung transplantation.