title: Inhibition of Murine Pulmonary Microvascular Endothelial Cell Apoptosis Promotes Recovery of Barrier Function under Septic Conditions.
abstract: Sepsis is characterized by injury of the pulmonary microvasculature and the pulmonary microvascular endothelial cells (PMVEC), leading to barrier dysfunction and acute respiratory distress syndrome (ARDS). Our recent work identified a strong correlation between PMVEC apoptosis and microvascular leak in septic mice in vivo, but the specific role of apoptosis in septic PMVEC barrier dysfunction remains unclear. Thus, we hypothesize thatPMVEC apoptosis is likely required for PMVEC barrier dysfunction under septic conditions in vitro. Septic stimulation (mixture of tumour necrosis factorα, interleukin 1β, and interferonγ[cytomix]) of isolatedmurinePMVEC resulted in a significant loss of barrier function as early as 4 h after stimulation, which persisted until 24 h. PMVEC apoptosis, as reflected by caspase activation, DNA fragmentation, and loss of membrane polarity, was first apparent at 8 h after cytomix. Pretreatment of PMVEC with the pan-caspase inhibitor Q-VD significantly decreased septic PMVEC apoptosis and was associated with reestablishment of PMVEC barrier function at 16 and 24 h after stimulation but had no effect on septic PMVEC barrier dysfunction over the first 8 h. Collectively, our data suggest that early septic murine PMVEC barrier dysfunction driven by proinflammatory cytokines is not mediated through apoptosis, but PMVEC apoptosis contributes to late septic PMVEC barrier dysfunction.
authors.affiliation: Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
authors.forename: Lefeng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Brock
authors.affiliation: Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
authors.forename: Sean E
authors.identifier: 0000-0003-4791-1576
authors.initials: SE
authors.lastname: Gill
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases; D053938:DNA Fragmentation; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D051379:Mice; D011804:Quinolines / Q000494:pharmacology; D018805:Sepsis / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020169:Caspases