Chronic plasminogen activator inhibitor-1 (PAI-1) overexpression dampens CD25+ lymphocyte recruitment after lipopolysaccharide endotoxemia in mouse lung.
BACKGROUND
Plasma plasminogen activator inhibitor-1 (PAI-1) level rises during sepsis and confers a worse prognosis. PAI-1 participation to sepsis has been poorly documented and was mainly associated with fibrin deposits. Beside fibrin deposits, increased tissue PAI-1 expression may contribute to the poor outcome of endotoxemia through other mechanisms.


OBJECTIVE
During lipopolysaccharide (LPS) challenge, the role of PAI-1 in the early phase of inflammation was examined in the lungs of transgenic mice that either overexpress or lack the PAI-1 gene (PAI-1Tg or PAI-1(-/-)).


RESULTS
Analysis of leukocytes revealed that neutrophil and macrophage infiltrations did not differ for PAI-1Tg and wild-type (WT) mice. Remarkably, CD25+ lymphocyte infiltration was totally blunted in PAI-1Tg lungs and inversely correlated with fibrin depositions. In parallel, mRNA levels of the regulatory T cell (Treg) markers FoxP3, CTLA-4, and GITR were significantly lower in PAI-1Tg than in WT lungs after LPS challenge. These data are supported by opposite results in PAI-1(-/-) lungs. The systemic compartments (spleen and peripheral blood) showed no decrease in CD25+, CD4+ CD25+ lymphocytes, and Treg markers in PAI-1Tg mice after LPS injection compared with WT mice. In addition, plasma and lung concentrations of interleukin-6 (IL-6) and macrophage inflammatory protein-1alpha (MIP-1alpha) were significantly higher in PAI-1Tg mice than WT mice.


CONCLUSIONS
Our results suggest that chronic tissue PAI-1 overexpression influences the early phase of the inflammatory response during endotoxemia through the control of T lymphocyte traffic.
Poggi
M
M
Faculté de Médecine, Aix-Marseille Université, Marseille, France.
Paulmyer-Lacroix
O
O
Verdier
M
M
Peiretti
F
F
Bastelica
D
D
Boucraut
J
J
Lijnen
H R
HR
Juhan-Vague
I
I
Alessi
M C
MC
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D060908:CTLA-4 Antigen; D054405:Chemokine CCL3 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005337:Fibrin / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D058258:Serpin E2; D015843:Serpins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; C106544:Tnfrsf18 protein, mouse; C433788:lipopolysaccharide, E. coli O26-B6; D007371:Interferon-gamma; D005337:Fibrin