Better Understanding of Organ Dysfunction Requires Proteomic Involvement Xiangdong Wang,*,†,‡ Kenneth B. Adler,§ Irshad H. Chaudry,| and Peter A. Ward⊥ Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, China, Department of Molecular Biomedical Science, North Carolina State University, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, North Carolina 27606, Department of Surgery, Microbiology, Physiology and Biophysics, Center for Surgical Research, University of Alabama at Birmingham, G094 Volker Hall, 1670 University Blvd., Birmingham, Alabama 35294-0018, and Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109 Received December 7, 2005
Abstract: Organ dysfunction is defined as a systemic consequence of acute and chronic diseases, a critical and important phase of disease development. The mortality of patients with severe illness is highly correlated with the number and duration of dysfunctional organs. There is still not an efficient and specific therapy to improve the prognosis of patients with organ dysfunction, due to the complexity and severity of the disease. There is a great need to understand molecular mechanisms of the disease, identify disease-related biomarkers, and validate therapeutic effects. Thus, it is important to have a special attention from proteomic scientists to explore the combination between advanced proteomic biotechnology, clinical proteomics, tissue imaging and profiling, and organ dysfunction score systems, to improve the clinical outcomes of these patients. Keywords: organ dysfunction • MODS • proteomics • biomarkers • prognosis
MODS is a severe form of organ dysfunction,1 since mortality is strongly correlated with the number of organs or systems failing,2,3 as well as patient age and duration of organ failure. The mortality rate of patients with multiple organ dysfunctions is between 30% and 100%, depending on these factors. Early scoring systems to define MODS severity focused primarily on survival prediction or the presence or absence of organ failure, while recent years have seen the development of newer models able to describe the evolution of individual and multiple organ dysfunction.4 MODS is often associated with trauma, sepsis, hemorrhagic shock, bacterial pneumonia, acute pancreatitis, and infection. Although efforts directed toward potential therapeutic targets in these diseases are growing, most successful therapeutic interventions have been employed in * To whom correspondence should be addressed. E-mail:
[email protected]. † Zhongshan Hospital. ‡ Department of Molecular Biomedical Science, North Carolina State University. § College of Veterinary Medicine, North Carolina State University. | University of Alabama at Birmingham. ⊥ The University of Michigan Medical School.
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experimental studies. Therapeutic strategies recently suggested include antiinflammatory approaches,5 blockade of effects of complement activation products such as C5a,6 somatostatin,7 and multiple organ support therapy.8 There is a great need to understand molecular mechanisms of organ dysfunction, investigate similarities and variations between etiologies, identify biomarkers for diagnosis and monitoring the process, detecting therapeutic effects of new drugs, and following up the prognosis of patients with MODS. Proteomics has been suggested to be a powerful and important tool for the discovery and validation of biomarkers.9 The potential significance of proteomic applications for biomarker discovery has been extensively suggested in a number of diseases (e.g., cancer, cardiovascular disease, acute renal allograft rejection, radiation, and allergy). It has been suggested that integrating protein expression data from proteomic studies should be combined with clinical data such as histopathology, clinical functional measurements, medical imaging scores, patient demographics, and clinical outcomes.10 Most diseaserelated proteomic investigations into validation of biomarkers have focused on protein expression in biological processes and diseased tissues. By using laser capture microdissection, proteomic analysis can be performed in highly selected cells from complex tissues and correlated with disease-specific pathology, combining the morphological precision of microscopy with the power of molecular genetics, genomics, and proteomics.11 However, there still remains a great need to link those potential disease biomarkers with measurements of severity, number, and prognosis of organ dysfunction. The reason there is a specific need of proteomics research for MODS, as compared with the individual disease, is that MODS is the late phase of the disease, has a poor understanding and prognosis, and has no specific biomarkers to describe the progress of the disease. MODS has higher mortality and morbidity and more influencing factors in the pathogenesis, and more difficulty for clinicians to investigate than any single disease. The complex nature of organ dysfunction, involving several physiological systems and functional organs, attracts the attention of proteomic scientists and experts using multiplex measurements of numerous protein analytes in samples from multiple systems within an organ or multiple organs within a system. There has been a call for multiplex proteomic approaches to sepsis research to provide a better understanding 10.1021/pr050441n CCC: $33.50
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Figure 1. Proposal of experimental designs for proteomic investigations in organ dysfunction. Current diagnosis and prediction of multiple organ dysfunction are based on different score systems and clinician experience. There is a great need to apply proteomics in the medical and clinical area of MODS where disease, disease progression, and cause of disease can be investigated at a molecular level. Proteomics will be linked to disease and organ dysfunction, and the problem-solving progress. Organ dysfunction needs attention from proteomic scientists and more studies are needed that combine clinical proteomics, tissue imaging and profiling, and targeted proteomics studies with organ dysfunction score systems, to improve the prognosis of patients with MODS.
of disease diagnosis, progression, and optimization of therapeutic strategy.12 Experimental studies have demonstrated alterations of proteomic profiles in the nervous system of animals in response to septic injury. One protein found to be up-regulated after septic shock is a novel member of the hemerythrin family belonging to a group of non-heme-iron oxygen transport proteins,13 probably associated with the binding to oxygen and iron as result of an innate immune response of the nervous system to bacterial invasion. Clinical evidence also indicates the possibility of detecting differences of proteomic profiles between severe illnesses. To identify polypeptide patterns functioning as early indicators of graftversus-host disease, proteomic analysis of urine was performed in patients after hematopoietic stem cell transplantation in patients with sepsis.14 Of more than 1000 polypeptides detected, 16 were considered to be markers of early graft-versus-host disease, with 82% specificity and 100% sensitivity, as compared to those without the complication, and in sepsis patients 13 were identified with a specificity of 97% and a sensitivity of 100%. Understanding organ dysfunction requires more information on the correlation of these biomarkers with measures of organ dysfunction. There is still a great lack of MODS-specific biomarkers, although inflammatory markers (e.g., cytokines, chemokines, free radicals, adhesion molecules, and cell activation) have been discussed to associate with the development of the disease, to be interorgan signaling messages between origin and distant organs, and to improve diagnosis and prognosis of MODS.21,22 Most of these markers are protein-
based elements originated from blood.Changes in cellular proteomic profiles depend on the location, challenges, activation, duration and disease. For example, leukocytes play an important role in the progression of disease, and leukocytederived proteins are associated with the pathogenesis of the disease. Leukocyte activation causes production of inflammatory mediators, increased expression of cell surface adhesion molecules, and an increase in migration and infiltration, phagocytosis and degranulation, as well as receptor phosphorylation and signal transduction. Leukocyte proteomic analysis enables proteomic investigation of activated or nonactivated leukocytes to be highly focused in defined suborgans or specific signaling pathways, varying from fingerprinting to functioning parameters, human cell lines to primary leukocytes, nonactivated cells to inflammatory mediator-stimulated cells, in vitro culture to in vivo challenge, and animal models to human disease.15 Epithelial cells as tissue-resident cells play an important role in physiological and pathophysiological situations, with organ-, tissue-, type-, and function-specific patterns. Dysfunction of epithelial cells has been proposed to play a crucial role in the development of multiple organ dysfunction, associated with inflammatory processes.16 Further considerations on potential mechanisms of epithelial cell-involved development of multiple organ dysfunction has recently been addressed.17 Epithelial cells may be activated to produce a number of inflammatory mediators (e.g., oxygen-free radicals, nitric oxygen, and cytokines), leading to the compromise of cells and organs. Proteomic analysis has been used to study Journal of Proteome Research • Vol. 5, No. 5, 2006 1061
communications diseases in epithelial surfaces and identify novel prognostic, diagnostic, and therapeutic markers. Variations of sample preparations for epithelial proteomic analysis have been investigated as have similarities and differences in epithelial proteomics between different cells and organs. We have found that most disease-associated investigations of epithelial proteomics have focused on epithelial-origin cancer and that there was a significant gap in epithelial proteomic studies that looked at acute versus chronic organ injury, inflammation, and multiple organ dysfunction.18 Ideally, experimental designs for proteomic investigations in organ dysfunction should also be referenced to clinical variables, as shown in Figure 1. Each variable should be objective, specific to the organ in question, independent of treatment and individual patient factors, demonstrating easily repeatable characteristics that others had used to define organ failure.19 A number of organ dysfunction score systems are available for describing and quantitating the degree of organ dysfunction in critically ill patients, including The Multiple Organ Dysfunction Score, The Brussels Score, and The Sequential Organ Failure Assessment. Early systems focused primarily on survival prediction or the presence or absence of organ failure, while recent years have seen the development of newer models able to predict the evolution of individual and multiple organ dysfunction. It is important to clarify the severity and stage of the disease on the basis of the application of such systems in the ICU.3 Due to the severe condition of most patients with organ dysfunction, the collection of test samples should be readily available. The optimal locations for sampling should be the circulation, peritoneal cavity, and urine. Proteomics has received the attention of clinicians, as rapid progress within the proteomics field has opened up possibilities for direct intervention in the medical and clinical area where disease, disease progression, and cause of disease can be investigated at a molecular level.9,20 The link to disease and organ dysfunction, and the problem-solving progress currently ongoing in other research areas have been explored.20 On the other hand, organ dysfunction also needs attention from proteomic scientists and more studies are needed that combine clinical proteomics, tissue imaging and profiling, and targeted proteomics studies with organ dysfunction score systems, all of which have the potential to improve the prognosis of patients who suffer from this syndrome (Figure 1). It is exciting and possible to eventually see the replacement of pathological
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scores with biomarkers, even though it is still in the future. Organ dysfunction is defined as ‘‘a systemic consequence of both acute and chronic diseases” and a critical and important phase, with a mortality rate between 30% and 100%. There is a great need to link potential disease biomarkers with measurements of severity, number, and prognosis of organ dysfunction. Experimental designs for proteomic investigations in organ dysfunction should be referenced to clinical variables, demonstrating easily repeatable characteristics used to define organ failure.
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