Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
The tissue response to injury is a complex and evolutionarily-conserved process that is fundamental to many diseases. Due to the demands of gas exchange, the lungs represent a large interface with the environment (~70m2 in an adult human) with a very thin barrier separating the vascular space from the outside world (mean thickness 0.6µm). Inflammatory responses in the lungs face the unique challenge of balancing defense of this interface with the preservation of surface area for gas exchange. To achieve this, the host must identify occasional pathogens among a barrage of innocuous particles, then quickly generate a fierce, yet highly localized, response to kill the pathogen while maintaining adequate gas exchange, and finally repair the resulting damage but halt scar formation to minimize permanent loss of gas exchange surface. This seems like a tall order but the process works remarkably well most of the time; when it does not, the consequences are pneumonia, pathological inflammation, or runaway scarring — the key features of most lung diseases. Our laboratory examines the mechanisms that mobilize cells from the bone marrow to the lungs via the circulation in the context of human lung disease and relevant animal models. Current projects in the lab are in the following areas:
Host defense in invasive aspergillosis: Aspergillus species are among the most common environmental moulds and their airborne spores are inhaled daily by all humans. Despite this constant exposure, the vast majority of normal hosts clear the organism without developing any illness. Hosts with impaired immunity, however, can develop a life-threatening infection in the respiratory tract that can then disseminate to other organs. A long-standing area of investigation in our lab is the study of host defense mechanisms in a model of this infection in neutropenic animals.
Experimental therapy for Gram-negative bacterial pneumonia: Aerobic Gram-negative bacilli are the most common causes of nosocomial infections and their treatment is enormously complicated by the progressive rise of antibiotic-resistance in hospitals. In recent work using a murine model of Gram-negative bacterial pneumonia, we have identified a group of chemokine ligands that can be therapeutically harnessed to enhance defenses against these infections. Ongoing studies seek to develop this mechanism as a potential therapy for human infections.
Fibrocytes in fibrotic lung disease: Interstitial lung diseases are a heterogeneous group of lung diseases defined by chronic and multifocal inflammation and fibrosis. We and others have identified a bone marrow-derived circulating cell, named fibrocyte, that homes to the lungs in these illnesses, differentiates into fibroblasts and myofibroblasts and contributes to tissue fibrosis. In translational projects in the laboratory and clinic, we are investigating these cells as potential biomarkers and therapeutic targets in human interstitial lung disease.
Chen L, Zhang Z, Barletta KE, Burdick MD, Mehrad B. Heterogeneity of lung mononuclear phagocytes during pneumonia: contribution of chemokine receptors. Am J Physiol Lung Cell Mol Physiol. 2013;305(10):L702-11.
Barletta KE, Cagnina RE, Burdick MD, Linden J, Mehrad B. Adenosine A(2B) receptor deficiency promotes host defenses against gram-negative bacterial pneumonia. Am J Respir Crit Care Med. 2012;186(10):1044-50.
Mehrad B, Strieter RM. Fibrocytes and the pathogenesis of diffuse parenchymal lung disease. Fibrogenesis Tissue Repair. 2012;5 Suppl 1:S22.
Park SJ, Burdick MD, Mehrad B. Neutrophils mediate maturation and efflux of lung dendritic cells in response to Aspergillus fumigatus germ tubes. Infect Immun. 2012;80(5):1759-65.
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