Obliterative bronchiolitis or chronic lung allograft rejection: A basic science review

doi:10.1016/j.healun.2004.01.009

The Journal of Heart and Lung Transplantation

Volume 24, Issue 1, January 2005, Pages 3-19

https://doi.org/10.1016/j.healun.2004.01.009 Get rights and content

Section snippets

Ischemia-reperfusion injury

Cold-ischemic storage and warm reperfusion incite multiple inflammatory pathways that promote primary graft dysfunction. Pre-transplant organ injury also may occur before organ harvesting.7, 8, 9, 10 Cold-ischemic storage induces oxidative stress; formation of super-oxide anion, hydrogen peroxide, and hydroxyl radicals; and lipid peroxidation in endothelial cells, type-II alveolar cells, Clara cells, ciliated epithelial cells, and alveolar macrophages.8

During warm reperfusion, the inflamed

Antigen recognition and presentation

The 1st step in the alloimmune cascade is recognition of graft antigens as foreign. Alloantigens are processed and presented in association with major histocompatibility complex (MHC) molecules on the surface of the antigen-presenting cells (APCs). Recipient APCs are derived from hematopoietic stem-cell progenitors that have migrated from the bone marrow, and donor APCs reside in the graft at implantation. Antigen-presenting cells include macrophages, activated B cells, and dendritic cells.

Lymphocyte costimulation

Indirect antigen recognition initiates an adaptive immune response in the secondary lymphoid organs in which naı̈ve T cells encounter alloantigens offered by APCs. The α and β chains of the T-cell receptor bind suitable antigens in an MHC-specific manner, whereas the ξ chain of the CD3-signaling sub-unit initiates 1st-signal antigen recognition after T-cell receptor, MHC, and peptide interaction. Larger numbers of T-cell receptor, MHC II, and antigen interactions are required to fully activate

Compartmentalization of chronic rejection: the airway

It is not known why the airway is the target tissue in OB. All lung cells (including alveolar vasculature and epithelium) express MHC Class I proteins, the important alloantigens in animal and clinical studies of OB. Compartmentalization of the alloimmune response may be caused by dendritic-cell trafficking to airways, which may augment sampling of alloantigens along the respiratory tract. Alternatively, airway epithelial cell participation in host defense and in mucosal immunity may play an

Fibroproliferation: the final events

Fibroproliferation and irreversible airway obstruction may occur before or after airway epithelial-cell loss. Macrophages, the predominant cell of the lower airways and of the alveolar airspaces, secrete many cytokines including IL-6, TGF-β, and insulin-like growth factor (IGF), and other growth factors. The epithelium and myofibroblasts may also be a relevant source of profibrotic factors,79 which may be of recipient origin.

Platelet-derived growth factor (PDGF)-A, PDGF-B chains, and the

Future directions and final thoughts

The lung allograft is injured by the host through antigen-dependent and antigen-independent mechanisms during repeated episodes of rejection and infection. Elements of adaptive and of innate immunity contribute to alloimmunity and are linked through redundant regulatory pathways. Effective antagonism of both adaptive and innate responses ultimately may be required to inhibit chronic allograft rejection.

Therefore, efforts to decrease bronchiolitis obliterans must incorporate strategies to

Acknowledgements

The authors thank Jessica Sloan for assistance with key figures, the University of North Carolina Department of Pulmonary Medicine for ongoing support, and the transplant physicians and coordinators of the University of North Carolina Lung Transplant Team for critical review.

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Sauropus androgynus L. Merr.-A phytochemical, pharmacological and toxicological review
2020, Journal of Ethnopharmacology
Sauropus androgynus L. Merr is an underexploited perennial shrub traditionally used as a medicinal plant in South Asia and Southeast Asia. The plant is regarded as not just a green vegetable for diet, but as a traditional herb for certain aliments. For instance, it has traditionally been used to relieve fever, to treat ulcers and diabetes, to promote lactation and eyesight, and to reduce obesity.
This paper aims to review the botany, phytochemistry, ethnopharmacology, and pharmacological activities of S. androgynus, and discuss the known chemical constituents at work in S. androgynus-induced bronchiolitis obliterans for providing new ideas to the mechanism of the disease and pharmacology research of the plant.
The data presented in this review were collected from published literatures as well as the electronic databases of PubMed, CNKI, Web of Science, SCI finder, ACS, Science Direct, Wiley, Springer, Taylor, Google Scholar, and a number of unpublished resources, (e.g. books, and Ph.D. and M.Sc. dissertations).
The scientific literature indicates that S. androgynus is a valuable and popular herbal medicine whose nutritional value is also higher than that of other commonly used vegetables. Phytochemical analyses identified high content of fatty acids, flavonoids, and polyphenols as the major bioactive components in S. androgynus. Crude extracts and phytochemical compounds isolated from S. androgynus show a wide spectrum of in vitro and in vivo pharmacological activities such as antioxidant, anti-inflammatory, anti-ulcer, skin whitening, anti-diabetic, and immunoregulatory activities. The traditional use, such as increasing lactation, treating ulcers and diabetes, and reducing obesity, have been evaluated and studied with various methods. Numerous reports have revealed the unusual link between the consumption of S. androgynus and the induction of a chronic and irreversible obstructive disease (namely, bronchiolitis obliterans), indicating that the toxicity and side effects of this plant that is presently used in health care and medicine are a major area of concern.
Though little importance was attached to this green plant, S. androgynus has notable phytochemical constituents and various pharmacological activities including antioxidant, anti-inflammatory, and anti-obesity activities. Studies have firmly established the association between excessive consumption of the uncooked S. androgynus juice over a period of time and the occurrence of bronchiolitis obliterans. It is inadvisable to ingest excessive amounts of S. androgynus before fully understanding the pathogenesis and induction mechanism of this fatal disease. The phytochemistry of S. androgynus, its pharmacology for traditional use, S. androgynus-induced bronchiolitis obliterans still need further investigation.
A novel MyD88 inhibitor attenuates allograft rejection after heterotopic tracheal transplantation in mice
2019, Transplant Immunology
Citation Excerpt :
Our results are also in agreement with those of other studies showing the importance of epithelial cells in OB. It was previously reported that the respiratory airway epithelium is the major target of immunologic injuries [20]. Airway epithelial damage and injury to sub-epithelial structures probably play important roles in the development of OB [20].
After lung transplantation, the major complication limiting the long-term survival of allografts is obliterative bronchiolitis (OB), characterized by chronic rejection. Innate immune responses contribute to the development of OB. In this study, we used a murine heterotopic tracheal transplantation mouse model to examine the effects of a newtype of innate immune inhibitor, TJ-M2010–5.
Syngeneic tracheal grafts were transplanted heterotopically from C57BL/6 mice to C57BL/6 mice. Allografts from BALB/c mice were transplanted to C57BL/6 mice. The allograft recipients were treated with TJ-M2010–5, and anti-mouse CD154 (MR-1). The grafts were harvested at 7, 14, and 28 days and evaluated by histological and real-time RT-PCR analyses.
In untreated allografts, almost all epithelial cells fell off at 7 days and tracheal occlusion reached a peak at 28 days. However, the loss of the epithelium and airway obstruction were significantly improved in mice treated with TJ-M2010–5 combined with MR-1. The relative mRNA expression levels of pro-inflammatory cytokines were upregulated in allogeneic tracheal grafts, and treatment with the two drugs reduced the production of pro-inflammatory cytokines and infiltration of inflammatory cells.
In heterotopic tracheal transplantation models, TJ-M2010–5 combined with MR-1 could ameliorate the development of OB.
Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction
2016, American Journal of Transplantation
Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin-1 alpha (IL-1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4–21.8] vs. 2.8 [0.9–9.4] pg/mL, p < 0.01) and was significantly elevated within 3 months of developing bronchiolitis obliterans syndrome (8.3 [1.4–25.1] vs. 3.6 [0.6–17.1] pg/mL, p < 0.01), whereas high mobility group protein B1 remained unchanged. IL-1α positively correlated with elevated bronchoalveolar lavage IL-8 levels (r² = 0.6095, p < 0.0001) and neutrophil percentage (r² = 0.25, p = 0.01). Conditioned media from P. aeruginosa infected epithelial cells induced a potent pro-inflammatory phenotype in fibroblasts via an IL-1α/IL-1R-dependent signaling pathway. In conclusion, we propose that IL-1α may be a novel therapeutic target to limit Pseudomonas associated allograft injury after lung transplantation.
Clinical neurology in lung transplantation
2014, Handbook of Clinical Neurology
Lung transplantation is the only established therapeutic option for several end-stage respiratory diseases. Limited mostly by lack of suitable allografts, the results have measurably improved over the last decade. Numerous surgical and pharmaceutical improvements have had positive impact on outcomes.
The potential for critical care issues and the need for interdisciplinary management remains paramount. Cardiac, renal, and metabolic complications are frequently encountered in the acute postoperative phase. Allograft rejection and infectious diseases as well as problems related to immunosuppressive regimen are seen later after lung transplantation. Neurologic manifestations with a range of etiologies are discussed here in this context.
Suppression of bronchiolitis obliterans in allogeneic rat lung transplantation-Effectiveness of everolimus
2013, Experimental and Toxicologic Pathology
Citation Excerpt :
Long-term outcome after lung transplantation (LTX) depended on the development of bronchiolitis obliterans (BO), a manifestation of chronic allograft rejection that affects more than 50% of recipients who survive the early post-transplant period (Trulock et al., 2007; Gourishankar and Halloran, 2002). The underlying mechanism includes repeated injury and inflammation of graft epithelial cells and subepithelial structures of small airways leading to extensive fibroproliferation due to ineffective epithelial regeneration and aberrant tissue repair resulting in partial or complete occlusion of the bronchioles (Stewart et al., 2007; Neuringer et al., 2005). Acute rejection (AR) and lymphocytic bronchiolitis are the major risk factors for chronic rejection (CR) (Hachem, 2009).
Chronic rejection (CR) after lung transplantation (LTX) manifests pathologically by fibrotic airway remodelling and bronchiolitis obliterans (BO). The role of the mammalian target of rapamycin inhibitor everolimus in preventing this process is poorly understood.
A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to analyze the effect of everolimus (2.5 mg/kg/day) on the development of CR. Drug therapy began on postoperative day (POD) 0, 7 and 14 characterizing different grade of acute rejection (AR) of the allograft before drug treatment.
Non-treated recipients developed severe acute rejection (AR) and first signs of CR on POD 20 and a pronounced CR on POD 60. On POD 20, only application of everolimus from POD 0 to 60 significantly reduced acute inflammatory infiltration (p < 0.001). Independent of treatment scheme, everolimus suppressed the development of early signs of chronic alterations (POD 20). However, neither early (POD 7–60) nor late (POD 14–60) application of everolimus affected the progression of CR (POD 60). Only its initial treatment (POD 0–60) inhibited the development of BO and vasculopathy (p < 0.001). An additional finding was a decrease in body weight after drug application.
The effectiveness of everolimus after rat LTX depended on the grade of inflammation of the allograft before initiation of drug treatment. Only allografts with no or low grade AR benefit from long-term treatment with everolilmus in the prevention of BO after LTX. It could be speculated that conversion to an everolimus-based immunosuppression after LTX might only be successful in patients free of BO.
Interstitial pneumonitis and the risk of chronic allograft rejection in lung transplant recipients
2013, Chest
The presence of interstitial pneumonitis (IP) on surveillance lung biopsy specimens in lung transplant recipients is poorly described, and its impact on posttransplant outcomes is not established. The following study assessed the association of posttransplant IP with the development of bronchiolitis obliterans syndrome (BOS).
We examined all recipients of primary cadaveric lung transplants at our institution between January 1, 2000, and December 31, 2007 (N = 145). Patients had bronchoscopies with BAL, and transbronchial biopsies performed for surveillance during posttransplant months 1, 3, 6, and 12 as well as when clinically indicated. Patients were given a diagnosis of IP if, in the absence of active infection and organizing pneumonia, they showed evidence of interstitial inflammation and fibrosis on two or more biopsy specimens.
IP was a significant predictor of BOS (OR, 7.84; 95% CI, 2.84-21.67; P < .0001) and was significantly associated with time to development of BOS (hazard ratio, 3.8; 95% CI, 1.93-7.39; P = .0001) within the first 6 years posttransplant. The presence of IP did not correlate with a significantly higher risk of mortality or time to death. There was no association between the presence of IP and the development of or time to acute rejection.
The presence of IP on lung transplant biopsy specimens suggests an increased risk for BOS, which is independent of the presence of acute cellular rejection.

View all citing articles on Scopus

^☆: This work was supported by the National Heart, Lung, and Blood Institute.

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Current controversiesObliterative bronchiolitis or chronic lung allograft rejection: A basic science review☆

Section snippets

Ischemia-reperfusion injury

Antigen recognition and presentation

Lymphocyte costimulation

Compartmentalization of chronic rejection: the airway

Fibroproliferation: the final events

Future directions and final thoughts

Acknowledgements

First page preview

J Heart Lung Transplant

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Ann Thorac Surg

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Am J Pathol

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Hum Immunol

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Immunity

Am J Transplant

Immunity

J Heart Lung Transplant

Scar collagen deposition in the airways of allografts of lung transplant recipients

Am J Respir Crit Care Med

Bronchiolitis obliterans after human lung transplantation

Am J Respir Crit Care Med

Immunologic mechanisms underlying bronchiolitis obliterans

Curr Opin Organ Transplant

Ischemia-reperfusion-induced lung injury

Am J Respir Crit Care Med

Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome

Ann Thorac Surg

Dendritic cells and macrophages in lung allograftsa role in chronic rejection?

Am J Respir Crit Care Med

Oligoclonal CD4 T cell expansions in lung transplant recipients with obliterative bronchiolitis

Am J Respir Crit Care Med

Hierarchical contributions of allorecognition pathways in chronic lung rejection

Am J Respir Crit Care Med

T-cell and major histocompatibility complex requirements for obliterative airway disease in heterotopically transplanted murine tracheas

Transplantation

Indirect recognition and antibody production against a single mismatched HLA-A2-transgenic molecule precede the development of obliterative airway disease in murine heterotopic tracheal allografts

Transplantation

Indirect recognition of minor histocompatibility antigens presented by recipient APC within draining lymph nodes promotes obliterative airways disease following tracheal allotransplantation

Am J Transplant

Indirect recognition of donor HLA class I peptides in lung transplant recipients with bronchiolitis obliterans syndrome

Transplantation

Rhinovirus infection induces major histocompatibility complex class I and costimulatory molecule upregulation on respiratory epithelial cells

J Infect Dis

Prolonged ischemia is associated with more pronounced rejection in the lung allograft

Ann Thorac Surg

Expression of MHC antigens in normal human lungs and transplanted lungs with obliterative bronchiolitis

Transplantation

MHC class II and ICAM-1 expression and lymphocyte subsets in transbronchial biopsies from lung transplant recipients

Transplantation

The immunohistopathology of obliterative bronchiolitis following lung transplantation

Transplantation

Specific immune responses against airway epithelial cells in a transgenic mouse-trachea transplantation model for obliterative airway disease

Transplantation

Bronchial epithelial cell B7-1 and B7-2 mRNA expression after lung transplantationa role in allograft rejection?

Eur Respir J

Current controversies
Obliterative bronchiolitis or chronic lung allograft rejection: A basic science review☆