The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.

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Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications.

Bronchiolitis obliterans (BO) is a major cause of allograft dysfunction in lung and heart lung transplant recipients. Clinically, progressive airflow limitation develops because of small airway obstruction. The disease has a variable course. Some patients experience rapid loss of lung function and respiratory failure. Others experience either slow progression or intermittent loss of function with long plateaus during which pulmonary function is stable. Histologic confirmation is difficult because transbronchial biopsy specimens often are not sufficiently sensitive for diagnosis. Because BO is difficult to document histologically, in 1993 a committee sponsored by the International Society for Heart and Lung Transplantation (ISHLT) proposed a clinical description of BO, termed bronchiolitis obliterans syndrome (BOS) and defined by pulmonary function changes rather than histology. Although this system does not require histologic diagnosis, it does recognize it. Transplant centers worldwide have adopted the BOS system as a descriptor of lung allograft dysfunction. This allows centers to use a common language to compare program results. In the years since publication of the BOS system, transplant scientists have studied basic and clinical aspects of lung transplant BO. In this document, we update and summarize new information obtained from this research and incorporate, where appropriate, the results into the BOS criteria. The document will include the following topics: (1) criteria for BOS, (2) BOS considerations in pediatric patients, (3) risk factors for BOS, (4) pathology of BO, (5) surrogate markers for BOS, (6) confounding factors in making a BOS diagnosis, and (7) assessment of response to treatment of BOS.

Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria.

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality among transplant recipients. For the purpose of developing consistent reporting of CMV in clinical trials, definitions of CMV infection and disease were developed and published. This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV.

Definitions of Cytomegalovirus Infection and Disease in Transplant Recipients

Summary: Following primary infection, human cytomegalovirus (HCMV) establishes lifelong latency and periodically reactivates without causing symptoms in healthy individuals. In the absence of an adequate host-derived immune response, this fine balance of permitting viral reactivation without causing pathogenesis is disrupted, and HCMV can subsequently cause invasive disease and an array of damaging indirect immunological effects. Over the last decade, our knowledge of the immune response to HCMV infection in healthy virus carriers and diseased individuals has allowed us to translate these findings to develop better diagnostic tools and therapeutic strategies. The application of these emerging technologies in the clinical setting is likely to provide opportunities for better management of patients with HCMV-associated diseases.

Immunobiology of Human Cytomegalovirus: from Bench to Bedside

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS.

A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations.

The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS.

The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention.

Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction

/pdf/an-international-ishlt-ats-ers-clinical-practice-guideline-r5q714354s.pdf

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Obliterative bronchiolitis after lung and heart-lung transplantation: An analysis of risk factors and management

Indirect effects of cytomegalovirus (CMV) infections in lung transplant recipients (LTX) have not previously been described in detail. We compared spirometric results, development of chronic rejection, rates of respiratory superinfections, and mortality as long as 2 yr after transplantation, between 62 LTX who never developed CMV (CMV− ) and 56 LTX with a history of CMV pulmonary infections (CMV+ ). Initial spirometric parameters were near identical for both groups, but determinations ⩾ 6 months after transplantation showed that expiratory flows of the CMV+ were significantly reduced. Actuarial prevalences of chronic allograft rejection (CR) at 2 yr were highest among CMV+ with biopsy-proved pneumonitis (74%) compared with 22% among CMV− (p < 0.038). Bacterial or fungal pneumonias developed in 58.9% of the CMV+, whereas the rate among CMV− was 38.7% (p < 0.05). Only 36% of LTX with CMV pneumonitis lived 2 yr compared with 70% survival for CMV− (p < 0.016). Ganciclovir treatment of CMV infections decreased...

Shari L. Similo

Papers

Obliterative bronchiolitis after lung and heart-lung transplantation: An analysis of risk factors and management

Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients.