Abstract
Viral pneumonias are a major cause of morbidity and mortality, owing in part to dysregulated excessive lung inflammation, and therapies to modulate host responses to viral lung injury are urgently needed. Protectin conjugates in tissue regeneration 1 (PCTR1) and protectin D1 (PD1) are specialized pro-resolving mediators (SPMs) whose roles in viral pneumonia are of interest. In a mouse model of Respiratory Syncytial Virus (RSV) pneumonia, intranasal PCTR1 and PD1 each decreased RSV genomic viral load in lung tissue when given after RSV infection. Concurrent with enhanced viral clearance, PCTR1 administration post-infection, decreased eosinophils, neutrophils, and NK cells, including NKG2D+ activated NK cells, in the lung. Intranasal PD1 administration post-infection decreased lung eosinophils and Il-13 expression. PCTR1 increased lung expression of cathelicidin anti-microbial peptide and decreased interferon-gamma production by lung CD4+ T cells. PCTR1 and PD1 each increased interferon-lambda expression in human bronchial epithelial cells in vitro and attenuated RSV-induced suppression of interferon-lambda in mouse lung in vivo. Liquid chromatography coupled with tandem mass spectrometry of RSV-infected and untreated mouse lungs demonstrated endogenous PCTR1 and PD1 that decreased early in the time course while cysteinyl-leukotrienes (cys-LTs) increased during early infection. As RSV infection resolved, PCTR1 and PD1 increased and cys-LTs decreased to pre-infection levels. Together, these results indicate that PCTR1 and PD1 are each regulated during RSV pneumonia, with overlapping and distinct mechanisms for PCTR1 and PD1 during the resolution of viral infection and its associated inflammation.
Highlights
The resolution of inflammation is an actively regulated process in which specialized pro-resolving mediators (SPMs) play a prominent role
Because protectin conjugates in tissue regeneration 1 (PCTR1) and protectin D1 (PD1) are present in lung tissue [13, 14] and PD1 reduced viral burden of influenza [23], we evaluated whether PCTR1 or PD1 could facilitate host resolution of Respiratory Syncytial Virus (RSV) infection in this model
Since exogenous PCTR1 and PD1 administered on day 3 p.i. led to reduced genomic viral load and decreased interstitial lung inflammation when measured on day 6 p.i., we evaluated whether endogenous production of protectins was altered during this self-limited model of RSV infection
Summary
The resolution of inflammation is an actively regulated process in which specialized pro-resolving mediators (SPMs) play a prominent role. SPMs are endogenous lipid mediators that include lipoxins, resolvins, maresins, and protectins, which are enzymatically produced from essential polyunsaturated fatty acids [1]. Because of structural similarities between PCTRs and other cysteinyl-SPMs (cys-SPMs) such as maresin conjugates in tissue regeneration, PCTR1 is proposed to be subsequently converted to PCTR2 by g-glutamyl transferase, followed by conversion to PCTR3 by dipeptidases [9]. Of note, this biosynthetic pathway can be influenced by neuronal stimuli such as acetylcholine [10]. Protectins act through G-coupled receptors [11] and intracellular mediators such as TNF receptor associated factor 3 [12]
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