Bacterial pneumonia triggers an exuberant host response with excessive inflammation, oxidative stress, and epithelial cell damage culminating in ARDS. At present, therapeutic interventions to treat ARDS remain limited to lung-protective strategies, as newer molecular mechanism-driven therapeutic interventions have not yet emerged. The specific pathways involved in the evolution of epithelial damage remain elusive. In preliminary experiments, we discovered that a mitochondria-specific phospholipid, cardiolipin (CL), is a critical damage signal that produces severe epithelial lung injury. We observed that after bacterial infection of murine lung epithelial cells or mice, CL transmigrates from the inner to the outer mitochondrial membrane where it acts as a novel signal for autophagy of mitochondria, mitophagy. We also showed that bacterial infection induces cytochrome c (cyt c)-mediated CL peroxidation as a pivotal step in apoptosis. Thus peroxidation of externalized CL acts as a molecular switch that triggers the apoptotic machinery. Finally, we demonstrate that CL and oxidized CL (Clox) are released from injured host cells into circulation and act as mitochondria-derived damage associated molecular patterns (DAMP-CL) triggering innate and adaptive immune responses. Our central hypothesis is that bacterial infection stimulates the unmasking and release of mitochondrial Cls that are indispensible intracellular signals in accelerating mitophagy and apoptosis;upon release into circulation, Cls act as DAMP-CL inducing innate and adaptive immune responses.
The Specific Aims of the proposed studies are to determine the: 1. Mechanisms and signaling role of CL asymmetry and its collapse in bacterial-induced mitophagy in distal lung epithelia. 2. Molecular pathways of CL peroxidation and the design and application of small-molecule regulators that protect against bacterial? induced distal lung epithelial apoptosis. 3. Molecular identity of species of CUCLox as DAMP-CL in circulation. Based on the highly innovative concept that CL is a unique intra- and extra-cellular signal in mitophagy, apoptosis, and innate/adaptive immune responses in pulmonary epithelium, we will explore four new classes of regulators of CL signaling for the development of pulmonary protective drugs

Public Health Relevance

Bacterial pathogens cause cell damage leading to acute lung injury necessitating the development of new therapeutic interventions. This application explores a new lipid damage signal, cardiolipin, - induced by virulent bacteria - that eradicates lung mitochondria, causes cell death and induces immune responses. By deciphering cardiolipin signaling we propose novel small-molecule therapeutic protectors from lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL114453-01A1
Application #
8643330
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2014-01-03
Project End
2018-12-31
Budget Start
2014-01-03
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$380,259
Indirect Cost
$130,259
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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