Role for phospholipid acyl chains and cholesterol in pulmonary infections and inflammation.
Bacterial and viral respiratory tract infections result in millions of deaths worldwide and are currently the leading cause of death from infection. Acute inflammation is an essential element of host defense against infection, but can be damaging to the host when left unchecked. Effective host defense requires multiple lipid mediators, which collectively have proinflammatory and/or proresolving effects on the lung. During pulmonary infections, phospholipid acyl chains and cholesterol can be chemically and enzymatically oxidized, as well as truncated and modified, producing complex mixtures of bioactive lipids. We review recent evidence that phospholipids and cholesterol and their derivatives regulate pulmonary innate and adaptive immunity during infection. We first highlight data that oxidized phospholipids generated in the lung during infection stimulate pattern recognition receptors, such as TLRs and scavenger receptors, thereby amplifying the pulmonary inflammatory response. Next, we discuss evidence that oxidation of endogenous pools of cholesterol during pulmonary infections produces oxysterols that also modify the function of both innate and adaptive immune cells. Last, we conclude with data that n-3 polyunsaturated fatty acids, both in the form of phospholipid acyl chains and through enzymatic processing into endogenous proresolving lipid mediators, aid in the resolution of lung inflammation through distinct mechanisms. Unraveling the complex mechanisms of induction and function of distinct classes of bioactive lipids, both native and modified, may hold promise for developing new therapeutic strategies for improving pulmonary outcomes in response to infection.
Department of Biochemistry and Molecular Biology, East Carolina Diabetes and Obesity Institute, East Carolina Heart Institute, Brody School of Medicine, East Carolina University (ECU), Greenville, North Carolina, USA.
Saame Raza
SR
Shaikh
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health (NIEHS/NIH), Research Triangle Park, North Carolina, USA.
Michael B
MB
Fessler
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA; gowdyk14@ecu.edu.
Kymberly M
KM
Gowdy
D056704:Adaptive Immunity; D000818:Animals; D002784:Cholesterol / Q000276:immunology / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology; D015525:Fatty Acids, Omega-3 / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000276:immunology / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D010084:Oxidation-Reduction; D010586:Phagocytes / Q000276:immunology; D010743:Phospholipids / Q000276:immunology / Q000502:physiology*; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000378:metabolism*; D011024:Pneumonia, Viral / Q000276:immunology / Q000378:metabolism*; D037661:Pulmonary Surfactant-Associated Proteins / Q000502:physiology; D051192:Receptors, Pattern Recognition / Q000276:immunology
D015525:Fatty Acids, Omega-3; D018836:Inflammation Mediators; D010743:Phospholipids; D037661:Pulmonary Surfactant-Associated Proteins; D051192:Receptors, Pattern Recognition; D002784:Cholesterol
immunity; n-3 PUFAs; oxidized phospholipids; respiratory infections