The pulmonary surfactant system of the lung is a lipid and protein complex that plays a central role in regulating the surface tension of the alveolar compartment and controlling innate immunity. The major lipid component of surfactant, dipalmitoyl-phosphatidylcholine, is the molecule responsible for the reduction of alveolar surface tension. Surfactant proteins A and D (SP-A and SP-D) are now understood to be important regulatory molecules involved in recognizing pathogens, facilitating their phagocytosis and regulating inflammation. We have recently discovered that two of the minor components of pulmonary surfactant, the anionic phospholipids phosphatidylglycerol (PtdGro) and phosphatidylinositol (PtdIns), are also potent regulators of inflammation and infection within the lung. These lipids are effective inhibitors of the activation of multiple Toll-like receptors (TLRs), which serve as sensors for microbial invasion and elicit inflammatory responses. The actions of PtdGro and PtdIns within surfactant appear to play a protective role in the lung by suppressing unnecessary tissue inflammation that would otherwise occur in response to non-infectious stimuli such as bacterial lipopolysaccharide present on ultrafine particles inhaled into the lung on a daily basis. We hypothesize that the role of PtdGro and PtdIns is to set a high threshold for the engagement of inflammation thereby preventing the lung from being chronically inflamed by casual exposure to airborne microbial products. In addition to suppressing inflammation, PtdGro and PtdIns also potently suppress infection of lung cells by respiratory syncytial virus (RSV) and influenza A virus (IFA). RSV is a major cause of hospitalization in the first two years of life. RSV and IFA also act as serious exacerbants of asthma and chronic obstructive pulmonary disease. The focus of this proposal is to understand how the anionic surfactant lipids exert their action. We plan to elucidate the molecular basis of the actions of the lipids by: 1) determining the structural basis of suppression of TLRs and viral infection, by using cell culture models of inflammation and infection;2) determining the efficacy of action of the anionic lipid in vivo in the context microbial ligand challenges to the lungs of mice;3) quantifying the action of the lipid antagonists against RSV and IFA in vitro and in vivo;4) defining the molecular mechanisms by which the anionic lipids suppress RSV and IFA infection. The work described in this proposal has direct relevance to treatment of bacterial and respiratory viral infections in children and adults, and important implications for treatment of individuals with asthma and chronic obstructive pulmonary disease.

Public Health Relevance

This work focuses on the newly discovered function of lipids found within the gas exchange regions of the lung. These lipids are potent suppressors of inflammation in the lung, and protect the organ from inadvertent activation of inflammatory processes. These lipids also have unexpected anti-viral activity against respiratory syncytial virus, which causes serious disease in newborns and individuals with asthma and chronic obstructive pulmonary disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL094629-01A1
Application #
7988086
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$351,000
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Kandasamy, Pitchaimani; Numata, Mari; Berry, Karin Zemski et al. (2016) Structural analogs of pulmonary surfactant phosphatidylglycerol inhibit toll-like receptor 2 and 4 signaling. J Lipid Res 57:993-1005
Fickes, Rachel; Voelker, Dennis R; Berry, Karin Zemski et al. (2016) Tandem mass spectrometry of novel ether-linked phospholipid analogs of anionic pulmonary surfactant phospholipids. Rapid Commun Mass Spectrom 30:2601-2606
Numata, Mari; Grinkova, Yelena V; Mitchell, James R et al. (2013) Nanodiscs as a therapeutic delivery agent: inhibition of respiratory syncytial virus infection in the lung. Int J Nanomedicine 8:1417-27
Numata, Mari; Kandasamy, Pitchaimani; Voelker, Dennis R (2012) Anionic pulmonary surfactant lipid regulation of innate immunity. Expert Rev Respir Med 6:243-6
Numata, Mari; Kandasamy, Pitchaimani; Nagashima, Yoji et al. (2012) Phosphatidylglycerol suppresses influenza A virus infection. Am J Respir Cell Mol Biol 46:479-87
Kandasamy, Pitchaimani; Zarini, Simona; Chan, Edward D et al. (2011) Pulmonary surfactant phosphatidylglycerol inhibits Mycoplasma pneumoniae-stimulated eicosanoid production from human and mouse macrophages. J Biol Chem 286:7841-53
Numata, Mari; Chu, Hong Wei; Dakhama, Azzeddine et al. (2010) Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus-induced inflammation and infection. Proc Natl Acad Sci U S A 107:320-5