DESCRIPTION (provided by applicant): Cigarette smoke induces emphysema through mechanisms which cause a loss of both matrix and cellular elements of the lung. The two main paradigms to explain emphysema postulate a) an imbalance of protease/antiproteases triggered by inflammation and b) a state of excessive alveolar endothelial apoptosis causing capillary regression. These two mechanisms would explain the loss of alveolar wall characterizing emphysema. However, the coexistence of an excessive lung structural cell apoptosis with that of an activated inflammatory state in emphysema and the hierarchy of their interaction have not yet been explained. We propose the excess of endothelial-monocyte-activating protein (EMAP II) is a unifying molecular mechanism to link apoptosis and inflammation in emphysema. EMAP II is a cytokine induced by conditions present in emphysematous lungs, being released from cells upon proteolytic cleavage by caspases and matrix metalloproteinases, which are known to participate in COPD. We identified CXCR3 as a functional receptor for EMAP II which mediates EMAP II-induced endothelial cell apoptosis and monocyte activation. Given the potent pro-apoptotic effect of EMAP II on endothelial cells, coupled with its ability to activate and recruit pro-inflammatory monocytes, we hypothesize that excessive EMAP II release in response to cigarette smoking engages both lung endothelial cell apoptosis and monocyte inflammatory activation, and therefore is a key molecular mediator of emphysema. We postulate that smoke induces EMAP II, which causes CXCR3- dependent endothelial apoptosis and activates monocytes. Activated caspases and matrix metalloproteinases may further increase EMAP II in the lung, amplifying damage signals that culminate in emphysema. These studies are relevant to human emphysema, as we measured increased EMAP II in the lungs of emphysema patients. Indeed, our data indicate that smoke-induced emphysema is preceded by EMAP II production and apoptosis in mice and lung-specific EMAP II increases are sufficient to cause lung apoptosis and emphysema. We will test the function of the secreted EMAP II and its receptor by neutralizing antibodies in cigarette smoke-induced emphysema in mice and conditional EMAP II transgenic overexpression in the lung. We developed 3 specific aims: 1. To determine whether EMAP II is a biomarker and molecular mediator of cigarette smoke-induced emphysema. 2 To investigate whether excessive lung EMAP II induces emphysema by triggering lung endothelial cell apoptosis or by recruitment of monocytes/macrophages, and 3. To determine the mechanism of EMAP II-induced cell apoptosis in primary human endothelial lung cells. These aims, if achieved are expected to position EMAP II as a therapeutic target and/or biomarker of emphysema. PROJECT NARRATIVE: We propose that our experimental plan will allow us to identify a key player in emphysema; EMAP II, which may become a biomarker measurable in biological fluids, and may also prove to be an attractive pharmacological target in a disease with scarce therapeutical options, and a high morbidity and mortality. The excessive EMAP II release stimulated by cellular stresses and ongoing protease activation would account for a vicious and worth targeting cycle of alveolar destruction in the lung. Furthermore, our work will allow to refine mechanisms of endothelial cell apoptosis while unifying the two theories in the field, that of excessive inflammation with that of excessive apoptosis.
|Effective start/end date||7/8/08 → 5/31/14|
- National Institutes of Health: $375,446.00
- National Institutes of Health: $368,800.00
- National Institutes of Health: $375,724.00
- National Institutes of Health: $380,751.00
small inducible cytokine subfamily E, member 1