Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK–mediated pathway

Kwak, Sang Hyun; Wang, Xue Qing; He, Qianbin; Fang, Wen‐Feng; Mitra, Sanchayita; Bdeir, Khalil; Ploplis, Victoria A.; Xu, Zhi; Idell, Steven; Cines, Douglas B.; Abraham, Edward

doi:10.1160/th05-12-0782

Cited by 44 publications

(37 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because apoptotic cell clearance is critical to the resolution of inflammation, our data suggest that PAI-1 may exacerbate inflammatory responses by blocking the clearance of apoptotic neutrophils, thereby allowing such neutrophils to become necrotic and to release their intracellular contents into the extracellular milieu. Our findings, together with previous studies demonstrating that PAI-1 enhances LPS induced neutrophil activation (22) and promotes the migration and infiltration of lymphocytes and neutrophils into inflammatory sites (19)(20)(21)27), demonstrate that PAI-1 has multiple proinflammatory roles that are independent of its participation in coagulation and microvascular thrombosis. We found that the enhanced neutrophil phagocytosis associated with PAI-1 deficiency can be abrogated by blocking LRP on macrophages with anti-LRP antibodies or the LRP-specific blocking peptide RAP, indicating that LRP participates in PAI-1 mediated modulation of efferocytosis.…”

Section: Discussionsupporting

confidence: 80%

“…Isolation of bone marrow neutrophils was as described (22,29). Peritoneal macrophages were isolated 5 days after i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies suggested that microvascular thrombosis associated with inhibition of fibrinolytic processes by PAI-1 and the role of PAI-1 as a chemotactic factor promoting the migration of lymphocytes and neutrophils into inflammatory sites contributed to its inflammatory effects (19)(20)(21). In addition, PAI-1 also appears to have intrinsic proinflammatory properties by potentiating Toll-like receptor 4 (TLR4) mediated activation of neutrophils (22).…”

mentioning

confidence: 99%

See 2 more Smart Citations

PAI-1 inhibits neutrophil efferocytosis

Park

Liu²,

Lorne³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

105

View full text Add to dashboard Cite

Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical for the resolution of inflammation. Plasma and tissue levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, are elevated in inflammatory conditions, including sepsis and acute lung injury, in which activated neutrophils accumulate in tissues and contribute to organ dysfunction. In this study, we explored the potential involvement of PAI-1 in modulating neutrophil efferocytosis. We found enhanced phagocytosis of viable PAI-1 deficient (PAI-1 ؊/؊ ) and of wild-type neutrophils treated with anti-PAI-1 antibodies. PAI-1 levels were decreased on the surface of apoptotic neutrophils and the enhanced phagocytosis of apoptotic wild-type neutrophils or of viable PAI-1 ؊/؊ neutrophils was diminished by preincubation with PAI-1. The increased phagocytosis associated with PAI-1 deficiency or blockade depended on both the lipoprotein receptor-related protein (LRP) and its ligand, calreticulin (CRT), because the LRP-mediated increase in phagocytosis of viable neutrophils induced by blockade of CD 47 was abrogated by PAI-1. CRT levels are increased on viable PAI-1 ؊/؊ neutrophils. While CRT colocalizes with PAI-1 on viable neutrophils, markedly diminished colocalization of PAI-1 and CRT was present on apoptotic neutrophils. Our data therefore indicate that PAI-1 serves as a novel ''don't eat me'' signal for viable and apoptotic neutrophils.calreticulin ͉ phagocytosis ͉ plasminogen activator inhibitor-1

show abstract

Section: Discussionsupporting

confidence: 80%

“…Isolation of bone marrow neutrophils was as described (22,29). Peritoneal macrophages were isolated 5 days after i.p.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

PAI-1 inhibits neutrophil efferocytosis

Park

Liu²,

Lorne³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

105

View full text Add to dashboard Cite

show abstract

“…Increased pulmonary levels of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) are present in ALI, and both uPA and PAI-1 are able to potentiate neutrophil activation (6 -10). Interaction of PAI-1 with the serine protease domain of uPA results in inhibition of the fibrinolytic, but not the proinflammatory activity of uPA, and appears to contribute to the development of microvascular thrombi and alveoli fibrin deposition that are characteristic histologic findings in ALI (6,7,10). Increased bronchoalveolar lavage levels of PAI-1 are associated with worse clinical outcome from ALI (11).…”

Section: A Cute Lung Injury (Ali)mentioning

confidence: 98%

Involvement of Vitronectin in Lipopolysaccaride-Induced Acute Lung Injury

Tsuruta¹,

Park²,

Siegal

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Vitronectin is present in large concentrations in serum and participates in regulation of humoral responses, including coagulation, fibrinolysis, and complement activation. Because alterations in coagulation and fibrinolysis are common in acute lung injury, we examined the role of vitronectin in LPS-induced pulmonary inflammation. Vitronectin concentrations were significantly increased in the lungs after LPS administration. Neutrophil numbers and proinflammatory cytokine levels, including IL-1β, MIP-2, KC, and IL-6, were significantly reduced in bronchoalveolar lavage fluid from vitronectin-deficient (vitronectin−/−) mice, as compared with vitronectin+/+ mice, after LPS exposure. Similarly, LPS induced increases in lung edema, myeloperoxidase-concentrations, and pulmonary proinflammatory cytokine concentrations were significantly lower in vitronectin−/− mice. Vitronectin−/− neutrophils demonstrated decreased KC-induced chemotaxis as compared with neutrophils from vitronectin+/+ mice, and incubation of vitronectin+/+ neutrophils with vitronectin was associated with increased chemotaxis. Vitronectin−/− neutrophils consistently produced more TNF-α, MIP-2, and IL-1β after LPS exposure than did vitronectin+/+ neutrophils and also showed greater degradation of IκB-α and increased LPS-induced nuclear accumulation of NF-κB compared with vitronectin+/+ neutrophils. These findings provide a novel vitronectin-dependent mechanism contributing to the development of acute lung injury.

show abstract

“…These results may be attributed to the ascribed function of PAI-1 in regulating fibrinolysis or a potential role of PAI-1 in mediating neutrophil recruitment signals, as was demonstrated in vitro. 55 In either case, these results suggest that PAI-1 function may prove to be a useful alternative target in the battle against bacterial pathogens.…”

Section: -22mentioning

confidence: 96%

Intracellular and extracellular serpins modulate lung disease

Askew

Silverman

2008

J Perinatol

View full text Add to dashboard Cite

An imbalance between peptidases and their inhibitors leads to pulmonary disease. Imbalances occur in the adult and the neonate at risk for a specific set of lung pathologies. Serpins (serine peptidase inhibitors) make up the major source of antipeptidase activity in the lung. The purpose of this review is to describe the serpin mechanism of inhibition, their roles in the normal and pathological lung and their potential as therapeutic agents.

show abstract

Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK–mediated pathway

Cited by 44 publications

References 20 publications

PAI-1 inhibits neutrophil efferocytosis

PAI-1 inhibits neutrophil efferocytosis

Involvement of Vitronectin in Lipopolysaccaride-Induced Acute Lung Injury

Intracellular and extracellular serpins modulate lung disease

Contact Info

Product

Resources

About