Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice
Objective and design
Cystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation. In this study, we investigated whether a lack of functional CFTR in neutrophils would promote lipopolysaccharide (LPS)-induced lung inflammation and injury.
Materials and methods
CFTR-inhibited or F508del-CFTR-mutated neutrophils were stimulated with LPS and cultured to evaluate production of cytokines and NF-κB activation. Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.
Pharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-κB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) production. Wild-type mice reconstituted with F508del neutrophils and bone marrow had more severe lung inflammation and injury after LPS challenge compared to wild-type mice receiving wild-type neutrophils or bone marrow reconstitution.
Lack of functional CFTR in neutrophils can promote LPS-induced acute lung inflammation and injury.
- Nguyen M, Pace AJ, Koller BH. Mice lacking NKCC1 are protected from development of bacteremia and hypothermic sepsis secondary to bacterial pneumonia. J Exp Med. 2007;204:1383–93. CrossRef
- Matthay MA, Su X. Pulmonary barriers to pneumonia and sepsis. Nat Med. 2007;13:780–1. CrossRef
- Courtney JM, Ennis M, Elborn JS. Cytokines and inflammatory mediators in cystic fibrosis. J Cyst Fibros. 2004;3:223–31. CrossRef
- Terheggen-Lagro SW, Rijkers GT, van der Ent CK. The role of airway epithelium and blood neutrophils in the inflammatory response in cystic fibrosis. J Cyst Fibros. 2005;4(Suppl 2):15–23. CrossRef
- Venkatakrishnan A, Stecenko AA, King G, Blackwell TR, Brigham KL, Christman JW, et al. Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;23:396–403.
- Blackwell TS, Stecenko AA, Christman JW. Dysregulated NF-kappaB activation in cystic fibrosis: evidence for a primary inflammatory disorder. Am J Physiol Lung Cell Mol Physiol. 2001;281:L69–70.
- Perez A, Issler AC, Cotton CU, Kelley TJ, Verkman AS, Davis PB. CFTR inhibition mimics the cystic fibrosis inflammatory profile. Am J Physiol Lung Cell Mol Physiol. 2007;292:L383–95. CrossRef
- Vij N, Mazur S, Zeitlin PL. CFTR is a negative regulator of NFkappaB mediated innate immune response. PLoS One. 2009;4:e4664. CrossRef
- Di A, Brown ME, Deriy LV, Li C, Szeto FL, Chen Y, et al. CFTR regulates phagosome acidification in macrophages and alters bactericidal activity. Nat Cell Biol. 2006;8:933–44. CrossRef
- Painter RG, Valentine VG, Lanson NA Jr, Leidal K, Zhang Q, Lombard G, et al. CFTR expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry. 2006;45:10260–9. CrossRef
- Thomas GR, Costelloe EA, Lunn DP, Stacey KJ, Delaney SJ, Passey R, et al. G551D cystic fibrosis mice exhibit abnormal regulation of inflammation in lungs and macrophages. J Immunol. 2000;164:3870–7.
- Bruscia EM, Zhang PX, Ferreira E, Caputo C, Emerson JW, Tuck D, et al. Macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator−/− mice. Am J Respir Cell Mol Biol. 2009;40:295–304. CrossRef
- Corvol H, Fitting C, Chadelat K, Jacquot J, Tabary O, Boule M, et al. Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis. Am J Physiol Lung Cell Mol Physiol. 2003;284:L997–1003.
- Wine JJ. The genesis of cystic fibrosis lung disease. J Clin Invest. 1999;103:309–12. CrossRef
- Engelhardt JF, Zepeda M, Cohn JA, Yankaskas JR, Wilson JM. Expression of the cystic fibrosis gene in adult human lung. J Clin Invest. 1994;93:737–49. CrossRef
- Tirouvanziam R, Khazaal I, Peault B. Primary inflammation in human cystic fibrosis small airways. Am J Physiol Lung Cell Mol Physiol. 2002;283:L445–51.
- Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49. CrossRef
- Su X, Matthay MA, Malik AB.Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury. J Immunol. 2010;184:401–410
- Ma T, Thiagarajah JR, Yang H, Sonawane ND, Folli C, Galietta LJ, et al. Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest. 2002;110:1651–8.
- Sonawane ND, Hu J, Muanprasat C, Verkman AS. Luminally active, nonabsorbable CFTR inhibitors as potential therapy to reduce intestinal fluid loss in cholera. Faseb J. 2006;20:130–2.
- Song Y, Sonawane ND, Salinas D, Qian L, Pedemonte N, Galietta LJ, et al. Evidence against the rescue of defective DeltaF508-CFTR cellular processing by curcumin in cell culture and mouse models. J Biol Chem. 2004;279:40629–33. CrossRef
- Colledge WH, Abella BS, Southern KW, Ratcliff R, Jiang C, Cheng SH, et al. Generation and characterization of a delta F508 cystic fibrosis mouse model. Nat Genet. 1995;10:445–52. CrossRef
- Su X, Camerer E, Hamilton JR, Coughlin SR, Matthay MA. Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms. J Immunol. 2005;175:2598–605.
- Su X, Johansen M, Looney MR, Brown EJ, Matthay MA. CD47 deficiency protects mice from lipopolysaccharide-induced acute lung injury and Escherichia coli pneumonia. J Immunol. 2008;180:6947–53.
- Lefort J, Singer M, Leduc D, Renesto P, Nahori MA, Huerre M, et al. Systemic administration of endotoxin induces bronchopulmonary hyperreactivity dissociated from TNF-alpha formation and neutrophil sequestration into the murine lungs. J Immunol. 1998;161:474–80.
- Looney MR, Su X, Van Ziffle JA, Lowell CA, Matthay MA. Neutrophils and their Fc gamma receptors are essential in a mouse model of transfusion-related acute lung injury. J Clin Invest. 2006;116:1615–23. CrossRef
- Mocsai A, Abram CL, Jakus Z, Hu Y, Lanier LL, Lowell CA. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat Immunol. 2006;7:1326–33. CrossRef
- Armstrong DA, Major JA, Chudyk A, Hamilton TA. Neutrophil chemoattractant genes KC and MIP-2 are expressed in different cell populations at sites of surgical injury. J Leukoc Biol. 2004;75:641–8. CrossRef
- Matzer SP, Baumann T, Lukacs NW, Rollinghoff M, Beuscher HU. Constitutive expression of macrophage-inflammatory protein 2 (MIP-2) mRNA in bone marrow gives rise to peripheral neutrophils with preformed MIP-2 protein. J Immunol. 2001;167:4635–43.
- Tsujimoto H, Ono S, Mochizuki H, Aosasa S, Majima T, Ueno C, et al. Role of macrophage inflammatory protein 2 in acute lung injury in murine peritonitis. J Surg Res. 2002;103:61–7. CrossRef
- Gupta S, Feng L, Yoshimura T, Redick J, Fu SM, Rose CE Jr. Intra-alveolar macrophage-inflammatory peptide 2 induces rapid neutrophil localization in the lung. Am J Respir Cell Mol Biol. 1996;15:656–63.
- Goldblum SE, Hennig B, Jay M, Yoneda K, McClain CJ. Tumor necrosis factor alpha-induced pulmonary vascular endothelial injury. Infect Immun. 1989;57:1218–26.
- Burdon PC, Martin C, Rankin SM. The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner. Blood. 2005;105:2543–8. CrossRef
- Spight D, Zhao B, Haas M, Wert S, Denenberg A, Shanley TP. Immunoregulatory effects of regulated, lung-targeted expression of IL-10 in vivo. Am J Physiol Lung Cell Mol Physiol. 2005;288:L251–65. CrossRef
- Tabary O, Zahm JM, Hinnrasky J, Couetil JP, Cornillet P, Guenounou M, et al. Selective up-regulation of chemokine IL-8 expression in cystic fibrosis bronchial gland cells in vivo and in vitro. Am J Pathol. 1998;153:921–30. CrossRef
- Legssyer R, Huaux F, Lebacq J, Delos M, Marbaix E, Lebecque P, et al. Azithromycin reduces spontaneous, induced inflammation in DeltaF508 cystic fibrosis mice. Respir Res. 2006;7:134. CrossRef
- Karp CL, Flick LM, Park KW, Softic S, Greer TM, Keledjian R, et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat Immunol. 2004;5:388–92. CrossRef
- Doring G, Conway SP, Heijerman HG, Hodson ME, Hoiby N, Smyth A, et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J. 2000;16:749–67. CrossRef
- Scheid P, Kempster L, Griesenbach U, Davies JC, Dewar A, Weber PP, et al. Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence. Eur Respir J. 2001;17:27–35. CrossRef
- Davidson DJ, Dorin JR, McLachlan G, Ranaldi V, Lamb D, Doherty C, et al. Lung disease in the cystic fibrosis mouse exposed to bacterial pathogens. Nat Genet. 1995;9:351–7. CrossRef
- McKeon DJ, Cadwallader KA, Idris S, Cowburn AS, Pasteur MC, Barker H, et al. Cystic fibrosis neutrophils have normal intrinsic reactive oxygen species generation. Eur Respir J. 2010;35:1264–72.
- Painter RG, Marrero L, Lombard GA, Valentine VG, Nauseef WM, Wang G. CFTR-mediated halide transport in phagosomes of human neutrophils. J Leukoc Biol. 2010;87:933–42.
- Sonawane ND, Verkman AS. Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis. Bioorg Med Chem. 2008;16:8187–95. CrossRef
- Dechecchi MC, Nicolis E, Bezzerri V, Vella A, Colombatti M, Assael BM, et al. MPB-07 reduces the inflammatory response to Pseudomonas aeruginosa in cystic fibrosis bronchial cells. Am J Respir Cell Mol Biol. 2007;36:615–24. CrossRef
- Elizur A, Cannon CL, Ferkol TW. Airway inflammation in cystic fibrosis. Chest 2008;133:489–95.
- Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Volume 60, Issue 7 , pp 619-632
- Cover Date
- Print ISSN
- Online ISSN
- SP Birkhäuser Verlag Basel
- Additional Links
- Cystic fibrosis transmembrane conductance regulator
- Bone marrow transplantation
- Industry Sectors
- Author Affiliations
- 1. Cardiovascular Research Institute, University of California, San Francisco, HSW 825, 505 Parnassus AVE, San Francisco, CA, 94143-0130, USA
- 2. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- 3. Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA