Boston University Medical Campus
Pathology and Laboratory Medicine

Daniel G. Remick, MD

Professor Chairman of Pathology and Laboratory Medicine

Degree(s) -

Positions and Employment

MEMBERSHIP AND OFFICES IN PROFESSIONAL SOCIETIES American Society of Investigative Pathologists, United States and Canadian Academy of Pathology, Michigan Association of Medical Examiners, Shock Society, American Association of Immunologists

Research interests

The laboratory focuses on investigating the inflammatory response with particular emphasis on cytokines. We are attempting to determine how the inflammatory response results in tissue/organ injury and death. To achieve this goal the laboratory uses a variety of methods ranging from whole animal models to isolated cells with reporter gene constructs. The ultimate focus of the lab is to understand the reaction to inflammation so that it may be modulated to improve health outcomes. It should be specifically noted that the modulation may include either blocking excessive inflammation or augmenting immunosuppression. Common themes: The primary theme which ties together all of the projects is the careful measurement of cytokines. Cytokines are peptide mediators of the inflammatory response which represent critical components. They have been successfully modulated to improve health in patients with severe diseases. There are several discrete projects within the laboratory. Sepsis. Sepsis represents the host response to severe infections and results in substantial morbidity and mortality. The mortality for a septic patient

exceeds 30% even in the best care situations. It is also important to note that the mortality for sepsis is calculated on the basis of 28 days survival, rather than the typical five-year survival used for cancer patients. Consequently, the number of years of life lost with sepsis is substantial. Our laboratory attempts to decipher the mechanisms for sepsis induced organ injury and mortality. The studies use a combination of a cell based approaches, whole animal experiments, and exploration of biomarker profiles in patients. Previous work has demonstrated that patients who suffer traumatic injury are at markedly increased risk for the development of sepsis, and its subsequent mortality. We are collecting plasma from patients who suffered a severe traumatic injury in a longitudinal fashion in order to determine if there is a biomarker profile which predicts both the development of sepsis, and that the outcome once a patient becomes a septic.

Asthma. Asthma represents another significant inflammatory condition with tremendous annual health-care costs. Our laboratory has developed a novel model of asthma like a pulmonary inflammation. Among children in inner cities, the major allergen which induces asthma comes from cockroaches rather than dog or cat allergens, or pollen. We collected dust from the homes were children had asthma and used this to induce inflammation in a mouse. the model was remarkably robust and produced several of the features observed in patients with asthma including the pulmonary recruitment of eosinophils, neutrophils, as well as mucous hyperplasia, and airways hyperreactivity. We have begun to use this model to explore novel treatments for asthma. Tumor necrosis factor (TNF) is a poorly named inflammatory mediator which actually has little to do with the necrosis of tumors. However, it is an important regulator of many aspects of chronic inflammation. Inhibitors of TNF have been used for years in the treatment of chronic inflammatory conditions such as rheumatoid arthritis. We were one of the first labs to demonstrate that blocking the biological activity of TNF could improve asthma. Panel A in the figure shows a lung from an animal which has been treated with an antibody directed against TNF. This is essentially normal histology with very little inflammation. In contrast, panel B shows an animal which received a control antibody. There are several dark purple dots surrounding the blood vessels and airways. These purple areas represent the nuclei of the inflammatory cells which have been elicited as part of the asthmatic response. Regulation of ongoing inflammation Several aspects of the inflammatory response work together to induce a synthesis of specific inflammatory mediators. Previous work from our laboratory has demonstrated that a generation of oxidants following a stimulus will induce the synthesis of specific cytokines. The ongoing inflammation is generated when the first stimulus induces a site a kind, the site a kind and then induces reactive oxygen, and reactive oxygen subsequently further enhances cytokine production. We initiated studies to determine which portion of the promoter was responsible for sensing the presence of reactive oxygen. For the studies we cloned the promoter region for monocyte chemotactic protein one (MCP1) into a luciferase reporter system. Following transfection, the cells were stimulated with tumor necrosis factor in the presence of the antioxidant dimethyl sulfoxide (DMSO). As shown in the accompanying figure, the DMSO suppresses reporter activity up until the region of -2741 base pairs. This indicates that the oxidants sensing portion must be located within this region of the MCP one promoter. Many investigators to study the regulation of inflammation, but the majority of the studies have been performed by adding an inhibitor and then adding a stimulus. However, most patients come to see their physician once the inflammatory process has already started. We have initiated studies to begin to examine the mechanisms of hollow inflammation is regulated in an ongoing manner.

 

Clinical interests

My clinical duties include the performance of autopsies at both University school of medicine. This is an excellent opportunity to teach residents and medical students basic pathophysiology of disease. The autopsy can also provide important information to the clinicians who care for patients and also the families about why their loved one has died. In June, 2007 we performed an autopsy of a man who died unexpectedly, and we were able to definitively determine the cause of death.

Remick Lab Members

Bryan Belikoff
	MD/PhD Thesis Student Contact Info: bgb@bu.edu 617-414-7095
Jacqueline Bouchard
	PhD Thesis Student Contact Info: jcbouch@bu.edu #617-414-7051
Florin Craciun
	PhD Thesis Student Contact Info craciun@bu.edu 617-414-7032
Brian Japp
	Research Assistant  Contact Info  bmjapp@bu.edu #617-414-7078
Liz Schuller
	MA Student Lab Manager Contact Info: eschul@bu.edu  #617-414-7016
Lou Vaickus
	MD/PhD Thesis Student Contact Info lvaickus@bu.edu #617-414-7095

Recent publications:

1. Remick DG: Pathophysiology of sepsis, Am J Pathol 2007, 170:1435-1444 2. Osuchowski MF, Welch K, Siddiqui J, Remick DG: Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality, J Immunol 2006, 177:1967-1974 3. Osuchowski MF, Remick DG: The repetitive use of samples to measure multiple cytokines: The sequential ELISA, Methods 2006, 38:304-311 4. Kim J, McKinley L, Natarajan S, Bolgos GL, Siddiqui J, Copeland S, Remick DG: Anti-tumor necrosis factor-alpha antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust, Clin Exp Allergy 2006, 36:122-132 5. Granger J, Siddiqui J, Copeland S, Remick D: Albumin depletion of human plasma also removes low abundance proteins including the cytokines, Proteomics 2005, 5:4713-4718 6. Xing L, Remick DG: Mechanisms of dimethyl sulfoxide augmentation of IL-1 beta production, J Immunol 2005, 174:6195-6202

Current Funding

Contact information: Email is the best, remickd@bu.edu Positions currently available: We are not actively recruiting at this time.