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

Neuringer, Isabel P.; Chalermskulrat, Worakij; Aris, Robert M.

doi:10.1016/j.healun.2004.01.009

Cited by 34 publications

(29 citation statements)

References 148 publications

(121 reference statements)

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“…Survival of lung transplant recipients is limited by the development of bronchiolitis obliterans (BO), an irreversible condition that responds poorly to therapy and results in airway remodeling with obstructive and restrictive features (187). In the past few years, the role of MMPs in BO-induced lung remodeling has been examined.…”

Section: F Bronchiolitis Obliteransmentioning

confidence: 99%

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

Greenlee¹,

Werb²,

Kheradmand³

2007

Physiological Reviews

404

330

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The matrix metalloproteinases (MMPs), a family of 25 secreted and cell surface-bound neutral proteinases, process a large array of extracellular and cell surface proteins under normal and pathological conditions. MMPs play critical roles in lung organogenesis, but their expression, for the most part, is downregulated after generation of the alveoli. Our knowledge about the resurgence of the MMPs that occurs in most inflammatory diseases of the lung is rapidly expanding. Although not all members of the MMP family are found within the lung tissue, many are upregulated during the acute and chronic phases of these diseases. Furthermore, potential MMP targets in the lung include all structural proteins in the extracellular matrix (ECM), cell adhesion molecules, growth factors, cytokines, and chemokines. However, what is less known is the role of MMP proteolysis in modulating the function of these substrates in vivo. Because of their multiplicity and substantial substrate overlap, MMPs are thought to have redundant functions. However, as we explore in this review, such redundancy most likely evolved as a necessary compensatory mechanism given the critical regulatory importance of MMPs. While inhibition of MMPs has been proposed as a therapeutic option in a variety of inflammatory lung conditions, a complete understanding of the biology of these complex enzymes is needed before we can reasonably consider them as therapeutic targets.

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Section: F Bronchiolitis Obliteransmentioning

confidence: 99%

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

Greenlee¹,

Werb²,

Kheradmand³

2007

Physiological Reviews

404

330

View full text Add to dashboard Cite

show abstract

“…More recently, we have identified antecedent communityacquired respiratory viral infection as a distinct risk factor for chronic allograft dysfunction (7). Because these risk factors result in epithelial cell injury and allograft inflammation, our laboratory and others have suggested that an exaggerated or abnormal epithelial injury response initiates allograft inflammation and chronic allograft dysfunction (3,6,8,9).…”

mentioning

confidence: 98%

“…Chronic lung allograft dysfunction is characterized histologically by airway epithelial cell injury, mononuclear cell influx, and fibrous obliteration of the small airways, and is referred to as bronchiolitis obliterans (BO) (2,3). The clinical correlate of BO is bronchiolitis obliterans syndrome (BOS) and is defined functionally as a persistent worsening of airflow obstruction (4).…”

mentioning

confidence: 99%

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Mikols

Yan

Norris

et al. 2006

Am J Respir Crit Care Med

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Rationale: Bronchiolitis obliterans syndrome is the leading cause of chronic lung allograft dysfunction. We have demonstrated that respiratory viral infection is a bronchiolitis obliterans syndrome risk factor and virus-dependent injury induces expression of innate airway epithelial genes belonging to the interleukin (IL)-12 family. Thus, we hypothesized that epithelial cell IL-12 family members could mediate lung allograft dysfunction. Objectives: We used mouse and human allograft specimens to evaluate the role of epithelial cell IL-12 family members in allograft dysfunction associated with and without viral infection. Methods: Murine and human IL-12 family members were characterized and manipulated in allografts and then correlated with epithelial cell injury, immune cell accumulation, and collagen deposition. Results: In a mouse model of lung transplantation, concurrent viral infection and allogeneic transplantation increased epithelial injury and this was followed by exaggerated accumulation of macrophages and collagen deposition. This virus-driven allograft dysfunction was associated with an epithelial innate response manifested by a synergistic increase in the production of the macrophage chemoattractant IL-12 p80 (p80), but not IL-12 or IL-23. Blockade or overexpression of donor epithelial p80 resulted in a corresponding abrogation or enhancement of macrophage accumulation and allograft dysfunction. We extended these findings to human recipients with viral infection and transplant bronchitis and again observed excessive epithelial p80 expression that correlated with increased macrophage accumulation. Conclusions: These experiments support a role for an enhanced epithelial innate response as a central process in allograft dysfunction and identify the macrophage chemoattractant p80 as an innate epithelial effector of disease progression.

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“…2,18,19 The origins of chronic rejection are believed to be upstream events immediately following lung transplantation. 20 In an update to the BOS classifi cation system by the International Society of Heart & Lung Transplantation, greater credence is given to identifying patients at risk for BOS with the goal of establishing earlier interventions. 3,21 The present fi ndings suggest that awareness of IP has the potential to identify early BOS-prone patients at a stage where intervention may be benefi cial.…”

Section: Resultsmentioning

confidence: 99%

Interstitial Pneumonitis and the Risk of Chronic Allograft Rejection in Lung Transplant Recipients

Mihalek

Rosas

Padera

et al. 2013

Chest

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Lung transplantation remains the only curative option for end-stage lung diseases, such as cystic fi brosis and pulmonary fi brosis. 1 Despite a growing understanding of lung transplantation, the 5-year mortality for transplant recipients remains about 50%. 2 The majority of posttransplant complications occurring after the fi rst posttransplant year are attributable to chronic allograft rejection.Bronchiolitis obliterans syndrome (BOS) is the clinical manifestation of chronic allograft rejection. BOS is associated with numerous risk factors, including medication noncompliance, 3 cytomegalovirus (CMV) infection, 4,5 gastroesophageal refl ex disease (GERD), 6-10 acute cellular rejection, 11,12 and air pollution. 13 The incidence of interstitial pneumonitis (IP) on lung biopsy specimen is poorly described, and its impact on outcomes is not established. This study assessed the association of posttransplant IP with the development of BOS. Materials and Methods Study PopulationWe examined all recipients of primary cadaveric lung transplants at our institution between January 1, 2000, and December 31, 2007 (N 5 145), for evidence of IP on lung biopsy specimen. Clinical data were collected through December 31, 2010. Approval from our institutional review board (Partners Human Research Committee; protocol # 2007-P000334/3) was obtained prior to study initiation. Abbreviations: BOS 5 bronchiolitis obliterans syndrome; CMV 5 cytomegalovirus; GERD 5 gastroesophageal refl ux disease; HR 5 hazard ratio; IP 5 interstitial pneumonitis; IQR 5 interquartile range; TBB 5 transbronchial biopsy Care of Patients

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

Cited by 34 publications

References 148 publications

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Interstitial Pneumonitis and the Risk of Chronic Allograft Rejection in Lung Transplant Recipients

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