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The Proceedings of the American Thoracic Society 3:444-449 (2006)
© 2006 The American Thoracic Society

Mechanisms of Airway Obliteration after Lung Transplantation

Laurent P. Nicod

Clinic and Policlinic of Pneumology, Inselspital, Bern, Switzerland

Correspondence and requests for reprints should be addressed to Laurent P. Nicod, Clinic and Policlinic of Pneumology, Inselspital, CH 3010 Bern, Switzerland. E-mail: laurent.nicod{at}insel.ch

ABSTRACT

Post-transplant bronchiolitis obliterans, also called bronchiolitis obliterans syndrome, affects up to 50–60% of patients who survive 5 yr after surgery according to its clinical definition, which is based on the degree of obstructive airway disease. Alloimmune-independent and -dependent mechanisms produce injuries and inflammation of epithelial cells and subepithelial structures, leading to aberrant tissue repair. The triggering of innate immunity by various infections or chemical injuries after, for example, gastroesophageal reflux, may lead to the release of danger signals that are able to activate dendritic cells, a crucial link with adaptive immunity. Inflammation can also increase the expression and display of major histocompatibility alloantigens and thus favor the initiation of rejection episodes. These phenomena may be limited in time and location or may be protracted. Reducing the risk of alloimmune-independent factors may be as important as treating acute episodes of lung rejection. Excessive immunosuppression may be deleterious by increasing the risk of infection, thereby triggering innate and adaptive immunity. New potential therapeutic targets are emerging from the research performed on leukotriene receptors, chemokine receptors, and growth factors. Neutralizing these molecules reduces the initial mononuclear and polynuclear infiltrates or the subsequent fibroproliferative process and the neovascular changes, feeding this process.

Key Words: adaptive immunity • dendritic cells • infections • innate immunity

The term "bronchiolitis obliterans" (BO) is commonly used to describe a number of unrelated conditions whose common endpoint is functional obstruction of the bronchioles. BO was described by Reynaud in 1835 (1). Since that time, BO has been described after the inhalation of toxic fumes, as a consequence of respiratory infections in association with connective tissue disorders, and after bone marrow or lung transplantation. It seems that severe damage to bronchiolar epithelium may, during the repair phase, lead to excessive proliferation of granulation tissue and often irreversible, destructive fibrous scarring of small airways, which is to be differentiated from BO organizing pneumonia, whose process is far less destructive and often reversible (2). We focus here on post-transplant BO, first described in 1984 at Stanford University. These patients showed a progressive decline in FEV1 (3). Lung biopsies from these patients showed intraluminal polyps comprised of fibromyxoid granulation tissue and plaque of dense submucosal scar.

Because BO is difficult to document histologically, the International Society for Heart and Lung Transplantation proposed in 1993 a clinical classification of BO, termed bronchiolitis obliterans syndrome (BOS), and defined by pulmonary function changes rather than histology. This clinical classification widely used to describe BO was revised in 2002 (4). BOS affects up to 50 to 60% of patients who survive 5 yr after surgery, irrespective of the type of transplant procedure (5). The time between transplantation and onset of BOS can range from a few months to several years, but in most series, the median time to diagnosis is 16 to 20 mo. In most patients, BOS is a progressive process accompanied by recurrent lower respiratory tract infections that respond poorly to augmented immunosuppression, which by themselves may precipitate infectious episodes acting on innate and acquired immunity, worsening bronchiole injuries and causing undue repairs. BO, as detected by BOS, accounts for more than 30% of all deaths occurring after the third postoperative year (6). Survival at 5 yr after the onset of BOS is only 30 to 40%; this survival is 20 to 40% lower than the survival rate of patients without BOS (5).

PATHOGENESIS

The histopathologic features of BO suggest that injury and inflammation of epithelial cells and subepithelial structures of small airways lead to excessive fibroproliferation, seemingly due to ineffective epithelial regeneration and aberrant tissue repair (7) (Figure 1). A concept of inadequate "injury response" has been proposed, linking nonspecific injury secondary to non–major histocompatibility-dependent or alloimmune-independent mechanisms and those injuries to T-lymphocyte activation by major histocompatibility alloantigens- or alloimmune-dependent mechanisms (Table 1) (8). It is probably not sufficient to link these two types of mechanisms because they may lead to a "final common pathway" lesion in which various insults can lead to similar histologic results (9). One should consider the accumulating knowledge linking innate and acquired immunity. Most alloimmune-independent mechanisms are potential triggers of alloimmune mechanisms by enhancing major histocompatibility alloantigens in the graft and activating dendritic cells (DCs) from a tolerogenic state to a nontolerogenic state regarding memory T cells. These phenomena may be limited in time and in location in the lungs. This would explain why at the time of histologic diagnosis, the airway injuries may be temporarily heterogeneous with some airways, showing only cellular infiltrates, whereas some display active fibroplasia and or inactive fibrosis (Figure 2) (10).


Figure 1
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  		Figure 1. Steps involved in bronchiolitis obliterans (damage, cellular infiltration, matrix deposition, and vascular remodeling) with the major mediators involved early and growth factors later. FGF = fibroblast growth factor; IGF = insulin-like growth factor; IL = interleukin; MCP = macrophage chemotactic proteins; PDGF = platelet-derived growth factor; TGF = transforming growth factor. Images used courtesy of Dr. J.C. Pache, University of Geneva.

 

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  		TABLE 1. THEORIES OF CHRONIC REJECTION

 

Figure 2
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  		Figure 2. Links between innate and adaptive immunity in bronchiolitis obliterans genesis. Environmental factors may trigger lung innate immunity, and this can increase alloantigen expression by the graft and lead to the potential triggering of adaptive immunity. The intensity of these phenomena and duration might explain phases of active and inactive bronchiolitis obliterans (BO).

 
RISK FACTORS

Many risk factors have been described as probable or as potential risks due to the quality of data reflecting the information derived from retrospective studies and/or the experience of single centers (9) (Table 2).


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  		TABLE 2. POTENTIAL AND PROBABLE RISK FACTORS LEADING TO BRONCHIOLITIS OBLITERANS SYNDROME

 
Alloimmune-dependent Factors
Acute rejection is widely accepted as a risk factor for BO. Acute rejection induces immunologic injuries directed toward epithelial and endothelial cells, which lead to BO. The risk increases when the acute rejection is histologically severe or when it persists or recurs after treatment (11–13). Similarly, lymphocytic bronchitis and bronchiolitis, even in the absence of acute perivascular rejection, have been shown to predate BOS in a significant number of patients (14). Acute rejection occurring later in the postoperative period remains an important risk factor (14). The occurrence of BOS within 3 mo of treatment for rejection suggests that acute rejection may lead directly to airway obliteration.

Several lines of evidence suggest that HLA mismatch is involved in the pathogenesis of BOS. Patients with anti-HLA antibody pretransplantation have an increased incidence of acute rejection and BOS (15). Identification of anti-HLA antibodies directed toward these antigens in previously unsensitized recipients is associated with the development of BOS (16). Patients with BOS have lymphocytes in bronchoalveolar lavage fluid (BALF) (17) or in blood, directed toward donor-specific class I HLA-antigens. Expression of class I and class II HLA antigens and adhesion molecules by bronchial epithelial cells is up-regulated during chronic rejection (18).

Murine models have improved our understanding of the alloimmune factors. Lymphocytic inflammation of airways reproduces the bronchiolitis in humans. Infiltrating cells include CD4 and CD8 T cells (the latter in higher proportion early on), natural killer cells, and macrophages/DCs (19). Cellular infiltration and airway obliteration are likely dependent on host CD40 ligands and to a lesser degree on CD28 (20). Similar increase of CD40 is found in early and late acute rejection in humans (21). Blocking CD28–CD86 interaction between T cells and antigen-presenting cells with cytotoxic T lymphocyte antigen-4 immunoglobulin delays the epithelial injuries of BO. CC and CXC chemokines and their receptors play an important role in the recruitment of intragraft leukocytes. Using neutralizing anti-RANTES (regulated upon activation, normal T-cell expressed and secreted) antibody decreases the number of infiltrating T cells and prevents airway obliteration (22). Similarly, monocyte chemoattractant protein, acting through its receptor CCR2, is a potent chemoattractant for mononuclear cell recruitment and later airway obliteration (23). Leukotriene B4 (LTB-4) has a potent chemotactic activity, not only on granulocytes or monocytes but also on CD4 and CD8 lymphocytes. This activity is mediated through the G-protein–coupled seven-transmembrane-spanning receptor BLT-1. In BLT-1–deficient mice and in mice with a specific small molecule antagonist of BLT-1, it has been possible to markedly reduce T-cell trafficking and BO formation. BLT-1, which is up-regulated on T lymphocytes infiltrating human lung transplants with BO, is becoming a potential therapeutic target in lung transplant rejection and BO (24).

The role of antigen-presenting cells, in particular DCs, has not been elucidated. Endobronchial biopsies show that the bronchial epithelium of patients with BOS contains increased numbers of DCs (25, 26). Alveolar macrophages seem to require costimulatory molecules (CD80, CD86, CD40) during acute rejection, similar to those of DCs. These findings seem to be transient, especially in patients with stable BOS (21).

Alloimmune-independent Factors
The lung is constantly exposed to inhaled noxious particles, such as a wide array of irritants, bacterial and viral agents, or fungi. These agents can have a direct mechanical interaction with the epithelium or phagocytic cells in the airways (27, 28). The pathogens trigger pathogen recognition receptors and induce the release of inflammatory mediators by epithelial cells and other cells that are part of the innate immune system (e.g., monocytes/macrophages, neutrophils, eosinophils, natural killer cells, and cytotoxic cells) and DCs, which are a strong link between innate and adaptive immunity, when they are activated from a quiescent or tolerant stage into a mature active DC (29). The pathogen recognition receptors are composed of 11 Toll-like receptors (TLRs), which are extracellular or in the endosomes (TLR-3, -7, and -9) and of non–Toll-like receptors, such as Dectin-1 or the mannose receptor (30). The signals generated by these pathogen recognition receptors instruct for the nature and outcome of the immune response after encountering bacteria, fungi, or viruses. The role of TLR-4 polymorphism has been demonstrated to have an impact on outcome after human lung transplant with a decreased incidence of acute rejection and BOS for recipient heterozygous for Asp299Gly or Thr39911 (31). These functional polymorphisms are associated with endotoxin hyporesponsiveness. They lead to decreased rate of acute rejections and reduce the onset of BO. These data show how innate immunity influences long-term outcomes after human lung transplantation (31). IFN-{gamma} and transforming growth factor (TGF) genotypic susceptibility related to gene polymorphisms have also been described (32, 33).

Several studies have suggested that community-acquired respiratory viral infections are associated with the development of BOS (34–36). In a recent study, 21 episodes of viral infections were diagnosed. Univariate and multivariate time-dependent Cox regression analyses demonstrated that these groups of patients were more likely to develop BOS (34). Respiratory syncytial viruses, parainfluenza, influenza, and adenoviruses accounted for these episodes. These studies and animal models suggest that respiratory viral infections may initiate inflammatory cascades related to innate immunity and adaptive immunity that might trigger acute rejection.

A high proportion of post-transplant patients with active influenza and parainfluenza infections were diagnosed with acute rejection in two studies (37, 38). One can speculate that respiratory viral infections can initiate acute and chronic responses that may trigger the development of BO episodes or BO progression in lung transplant patients. The persistence of viruses may induce progressive chronic changes. We recently found patients who had rhinoviruses of a given genotype for more that 6 wk and rapidly progressive BO (unpublished data). This state of chronic carrier of respiratory viruses during immunosuppression deserves our attention, and multiplex polymerase chain reaction will be a valuable tool in these circumstances. Cytomegalovirus (CMV)-related illnesses have been implicated in chronic vascular rejection of nonpulmonary solid organ transplants. CMV pneumonitis was correlated with the development of BOS (11). CMV mismatch is reported as a risk factor for 1- and 5-yr mortality. The prospective surveillance of CMV antigenemia, the use of prophylactic or preemptive antiviral treatments, and changes in the immunosuppressive regimen have decreased the risk of CMV in the development of BOS (39, 40).

Bacterial and fungal infections are not known to contribute directly to the pathogenesis of BOS, although they may have numerous impacts on innate immunity and increase the risk of acute rejection and of BO (41).

Among the chemical injuries leading to possible airway inflammatory conditions and BO are those related to gastroesophageal reflux disease (GERD). GERD is common after lung transplant, in part due to intraoperative injuries to the vagal nerve and medication-induced gastroparesis. Afferent denervation of the airways diminishes the chronic cough associated with GERD. In a recent study, actuarial curves show the significantly reduced interval from transplant to BOS development in patients with high bronchoalveolar fluid bile acid levels (42). A prolonged contact time of aspirated gastric contents may lead to epithelial lung injuries. It is possible that it may play a role in augmenting the alloimmune response by creating a locally up-regulated inflammatory milieu.

Several additional factors have been proposed as risk factors for BOS. These factors include a history of smoking or asthma in the donor, but convincing data to support their role are lacking (12).

AIRWAY REMODELING DURING BO

BO results from a chronic immunologic or inflammatory insult to the allograft airways that causes granulation tissue formation that ends in fibroobliteration (43). During the time of injury and matrix degradation, matrix metalloproteinases (MMPs) are likely involved. Some of the 23 MMPs known are thought to be responsible for turnover of extracellular matrix in several lung diseases (44, 45). MMP-9 belongs to the gelatinases and has a relative molecular weight of 92 kD. It contributes to the migration of inflammatory cells through the extracellular matrix, basement membrane, and endothelial layer. The major specific inhibitors of MMPs are tissue inhibitors of metalloproteinases. An imbalance in the ratio of MMPs to tissue inhibitors of metalloproteinases may be critical in bronchial tissue destruction repair. An increased concentration of MMP-9 without a counterbalancing increase of tissue inhibitors of metalloproteinase-1 in BOS after lung transplantation has been found (46). MMP-9 expression and activity in BALF was strongly associated with polymorphonuclear neutrophils.

Cells typically involved in the fibroproliferative phase are fibroblast-like cells that express type III collagen messengers (47). Mediators found in murine models are profibrotic cytokines, such as platelet-derived growth factor, fibroblast growth factor, TGF-ß, insulin-like growth factor (IGF-1), and endothelin (ET)-1 (48). ET-1 is up-regulated during bacterial infections in lung transplant recipients (49). ET-1 has profibrotic properties and is involved in the airway remodeling of several inflammatory diseases. As in the heterotopic airway models in animals, increased BALF concentration of platelet-derived growth factors (50), IGF-1 (51), and TGF-ß (52) are found in human BOS.

Angiogenesis and vascular remodeling support fibroproliferative process, including diabetic retinopathy, pulmonary fibrosis, and rheumatoid arthritis (53). Significant aberrant angiogenesis was demonstrated in lung biopsy specimens from patients with BOS. BALF from patients with BOS shows significant angiogenic activity. Vascular remodeling associated with BOS lesions involves endothelial cells expressing CXCR2. The same authors demonstrated that the effects of the CXCR2/CXCR2-ligand biological axis are bimodal during BOS: early it affects neutrophil recruitment (i.e., during the ischemia/reperfusion injury phase), and later it affects vascular remodeling and angiogenesis (i.e., during the fibroproliferative phase) independent of neutrophil recruitment (54).

PREVENTION AND EARLY DETECTION

The new classification of BOS aims at early detection of BOS (55) and early therapy to stop or slow the progression of BOS. An interesting strategy may be to uncouple the association between acute rejection and BOS. Early intervention on BO may lead to stabilization in more than 80% of patients (13). Monitoring of lung function (56), BAL monitoring of neutrophils (57), measurement of MMP-9 (46), and analysis of volatile and nonvolatile markers originating from the respiratory tract may help to monitor flares of acute rejections to allow early treatment and prevention BO episodes.

New therapeutic approaches may be important to block flares of innate immunity. Azithromycin has been shown to be able to stabilize or even reverse airflow obstruction in BOS by its antiinflammatory action (58). Other similar approaches have to be found to prevent or block innate immunity triggering.

Another approach is to work on acquired immunity, although this approach presents the danger of enhancing the risks of persistent viral infections or bacterial or fungal infections. New immunosuppressors have modified the incidence and fate of BO, such as mycophenolate mofetil (59) or tacrolimus (60). Other modes of immunosuppression delivery (e.g., cyclosporine aerosols) have been successfully used (61).

Several groups are generating new data that show a better prognosis of BO and often long-term good quality of life for patients with BOS who are treated with the new compounds mentioned previously. Decreased immunosuppression during viral diseases has been seen with the use of preemptive treatment of viral infections like CMV and elective treatments of early or late acute rejections (62).

CONCLUSIONS

BO occurs after lung transplantation, often after repeated episodes of acute lung rejection. These acute rejection episodes follow the activation of adaptive immunity. The mismatch of HLA is responsible for some of these episodes, but other phenomena, such as viral infections, may lead to the activation of innate immunity. CMV and community-acquired respiratory viral infections are associated with the development of BO. Some inflammatory mechanisms are known to favor the development of BO. Gastroesophageal reflux with the aspiration of bile salts is probably one of the best illustrations of this type of event. Thus, various alloantigen and nonalloantigen mechanisms can lead to airway injuries and to the characteristically excessive and aberrant tissue repair of the injured epithelial and subepithelial structures. Targeting some of the molecules involved in inflammation and in tissue repair should bring new therapeutic prospects.

ACKNOWLEDGMENTS

The author thanks Mrs. Rahel Holderegger for the careful typing of this manuscript and Dr. J.C. Pache from the University of Geneva, Department of Pathology, for the kind gift of anatomopathologic pictures.

FOOTNOTES

Supported by Swiss National Science Foundation grant no. 310000-107659.

Conflict of Interest Statement: L.P.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form January 18, 2006; accepted in final form March 24, 2006)

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