Basic Science Research
Innate immunity helps to protect the lung against infection and is a critical component of diverse lung diseases. Our mission is to elucidate the mechanisms and functional significance of innate immune processes, with the goals of identifying factors that increase risks for lung diseases and designing new strategies for their treatment.
The Innate Immunity group at the Pulmonary Center focuses on local and systemic innate immune responses to infectious, environmental, and other challenges to the lung. Diseases of particular interest include acute respiratory infections (pneumonia and influenza), acute lung injury (ALI/ARDS), chronic obstructive pulmonary disease (COPD/emphysema), and pulmonary alveolar proteinosis. Further advances against these diseases are predicated upon breakthroughs in the understanding of innate immunity.
We study the contributions of innate immunity to lung disease using diverse approaches including genetic engineering, molecular and cell biology, and integrative physiology. One major focus of our work is the alveolar macrophage, particularly its development, fate, and functional roles as a resident innate immune cell. Another emphasis is the recruitment and activation of neutrophils as additional innate immunity effector cells enlisted when resident defenses in the lung are insufficient. Research is also illuminating the roles of structural, non-hematopoietic cells (such as alveolar epithelial cells, adipocytes and hepatocytes) in mediating local as well as systemic innate immune functions (such as the bone marrow production and release of leukocytes and the liver acute phase response). A consistent theme to this research is the molecular mechanisms mediating the expression of gene programs that drive innate immunity, such as the transcription factors coordinating the expression of cytokines, chemokines, colony stimulating factors, adhesion molecules, antimicrobial factors, and cytoprotective proteins. While initiating innate immune responses is essential to fighting infections, controlling these responses is equally important and essential to limiting lung injury, mediated for example by microRNAs and repressor proteins. Inflammatory injury results from exuberant innate immune activity in the lung, and the cellular and molecular mechanisms of repair and regeneration subsequent to lung injury represents an emerging research interest of the group.
Ongoing research projects:
- Alveolar macrophage kinetics and function.
- Neutrophil recruitment and activation in the lungs.
- Rheostat fine-tuning of innate immune responses (transcriptional and post-transcriptional mechanisms) to fight infection without excessive lung injury.
- The regulation and functional significance of hepatic acute phase responses during lung disease.
- Influence of adipokines and other adipose-derived signals on lung innate immunity.
- Repair of the injured lung, including roles of stem cells, cellular differentiation, proliferation, apoptosis, autophagy, and senescence.
- Lentiviral vectors for elucidating and manipulating innate immunity in the lungs.
- Alan Fine
- Michael Ieong
- Matthew Jones
- Darrell Kotton
- Joseph Mizgerd
- Lee Quinton
- Ross Summer
- Andrew Wilson
- Pittet, LA, Quinton LJ, Yamamoto K, Robson BE, Ferrari JD, Algül H, Schmid RM, Mizgerd JP. 2011. Earliest innate immune responses require macrophage RelA during pneumococcal pneumonia. Am J Respir Cell Mol Biol (in press).
- Wilson AA, Murphy GJ, Hamakawa H, Kwok LW, Srinivasan S, Hovav AH, Mulligan RC, Amar S, Suki B, Kotton DN. 2010. Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages. J Clin Invest 120:379-89.
- Walkey AJ, Rice TW, Konter J, Ouchi N, Shibata R, Walsh K, deBoisblanc BP, Summer R. 2010. Plasma adiponectin and mortality in critically ill subjects with acute respiratory failure. Crit Care Med 38:2329..
- Jones MR, Quinton LJ, Blahna MT, Neilson JR, Fu S, Ivanov AR, Wolf DA, Mizgerd JP. 2009. Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nat Cell Biol 11: 1157-63.
- Quinton LJ, Jones MR, Robson BE, Mizgerd JP. 2009. Mechanisms of the hepatic acute-phase response during bacterial pneumonia. Infect Immun 77:2417-26..
- Summer R, Fiack CA, Ikeda Y, Sato K, Dwyer D, Ouchi N, Fine A, Farber HW, Walsh K. 2009. Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease. Am J Physiol Lung Cell Mol Physiol 297:L432-8.
- Wilson AA, Kwok LW, Hovav AH, Ohle SJ, Little FF, Fine A, Kotton DN. 2008. Sustained expression of alpha1-antitrypsin after transplantation of manipulated hematopoietic stem cells. Am J Respir Cell Mol Biol 39:133-41.
- Mizgerd JP. 2008. Mechanisms of disease: Acute lower respiratory infection. N Engl J Med 358:716-727.
- Summer R, Little FF, Ouchi N, Takemura Y, Aprahamian T, Dwyer D, Fitzsimmons K, Suki B, Parameswaran H, Fine A, Walsh K. Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice. 2008. Am J Physiol Lung Cell Mol Physiol 294:L1035-42.
- Murphy J, Summer R, Wilson AA, Kotton DN, Fine A. 2008. The prolonged life-span of alveolar macrophages. Am J Respir Cell Mol Biol 38:380-5.