全部 标题 作者
关键词 摘要

OALib Journal期刊
ISSN: 2333-9721
费用:99美元

查看量下载量

相关文章

更多...
PLOS ONE  2013 

Important Role of Platelets in Modulating Endotoxin-Induced Lung Inflammation in CFTR-Deficient Mice

DOI: 10.1371/journal.pone.0082683

Full-Text   Cite this paper   Add to My Lib

Abstract:

Mutation of CFTR (cystic fibrosis transmembrane conductance regulator) leads to cystic fibrosis (CF). Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation) mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels). Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1), platelet activating factor (PAF), and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF), or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.

References

[1]  Su X, Looney MR, Su HE, Lee JW, Song Y, et al. (2011) Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice. Inflamm Res 60: 619–632.
[2]  Mattoscio D, Evangelista V, De Cristofaro R, Recchiuti A, Pandolfi A, et al. (2010) Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response. FASEB J 24: 3970–3980.
[3]  Ciabattoni G, Davi G, Collura M, Iapichino L, Pardo F, et al. (2000) In vivo lipid peroxidation and platelet activation in cystic fibrosis. Am J Respir Crit Care Med 162: 1195–1201.
[4]  O'Sullivan BP, Linden MD, Frelinger AL 3rd, Barnard MR, Spencer-Manzon M, et al. (2005) Platelet activation in cystic fibrosis. Blood 105: 4635–4641.
[5]  O'Sullivan BP, Michelson AD (2006) The inflammatory role of platelets in cystic fibrosis. Am J Respir Crit Care Med 173: 483–490.
[6]  Konstan MW, Byard PJ, Hoppel CL, Davis PB (1995) Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 332: 848–854.
[7]  Lands LC, Milner R, Cantin AM, Manson D, Corey M (2007) High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr 151: 249–254.
[8]  Vandendries ER, Furie BC, Furie B (2004) Role of P-selectin and PSGL-1 in coagulation and thrombosis. Thromb Haemost 92: 459–466.
[9]  Kuster LJ, Filep J, Frolich JC (1986) Mechanism of PAF-induced platelet aggregation in man. Thromb Res 43: 425–433.
[10]  Song Y, Sonawane ND, Salinas D, Qian L, Pedemonte N, et al. (2004) Evidence against the rescue of defective DeltaF508-CFTR cellular processing by curcumin in cell culture and mouse models. J Biol Chem 279: 40629–40633.
[11]  Su X, Looney M, Robriquet L, Fang X, Matthay MA (2004) Direct visual instillation as a method for efficient delivery of fluid into the distal airspaces of anesthetized mice. Exp Lung Res 30: 479–493.
[12]  Qian F, Deng J, Cheng N, Welch EJ, Zhang Y, et al. (2009) A non-redundant role for MKP5 in limiting ROS production and preventing LPS-induced vascular injury. EMBO J 28: 2896–2907.
[13]  Jacquot J, Tabary O, Clement A (2008) Hyperinflammation in airways of cystic fibrosis patients: what's new? Expert Rev Mol Diagn 8: 359–363.
[14]  Makam M, Diaz D, Laval J, Gernez Y, Conrad CK, et al. (2009) Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs. Proc Natl Acad Sci U S A 106: 5779–5783.
[15]  Yang J, Hirata T, Croce K, Merrill-Skoloff G, Tchernychev B, et al. (1999) Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil rolling and migration. J Exp Med 190: 1769–1782.
[16]  Frenette PS, Denis CV, Weiss L, Jurk K, Subbarao S, et al. (2000) P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J Exp Med 191: 1413–1422.
[17]  Furie B, Furie BC (2004) Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 10: 171–178.
[18]  Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM (2002) The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 30: S294–301.
[19]  Chang SW, Feddersen CO, Henson PM, Voelkel NF (1987) Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats. J Clin Invest 79: 1498–1509.
[20]  Beijer L, Botting J, Crook P, Oyekan AO, Page CP, et al. (1987) The involvement of platelet activating factor in endotoxin-induced pulmonary platelet recruitment in the guinea-pig. Br J Pharmacol 92: 803–808.
[21]  Rabinovici R, Esser KM, Lysko PG, Yue TL, Griswold DE, et al. (1991) Priming by platelet-activating factor of endotoxin-induced lung injury and cardiovascular shock. Circ Res 69: 12–25.
[22]  Stead RJ, Barradas MA, Mikhailidis DP, Jeremy JY, Hodson ME, et al. (1987) Platelet hyperaggregability in cystic fibrosis. Prostaglandins Leukot Med 26: 91–103.
[23]  Robert R, Carlile GW, Pavel C, Liu N, Anjos SM, et al. (2008) Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol 73: 478–489.

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133