Abstract
Inflammation is a major component of the vicious cycle characterizing cystic fibrosis (CF) pulmonary disease. If untreated, this inflammatory process irreversibly damages the airways, leading to bronchiectasis and ultimately respiratory failure. Anti-inflammatory drugs for CF lung disease appear to have beneficial effects on disease progression. These agents include oral corticosteroids and ibuprofen, as well as azithromycin, which, in addition to its antimicrobial effects, also possess anti-inflammatory properties. Inhaled corticosteroids, antioxidants, nutritional supplements, and protease inhibitors have a limited impact on the disease. Adverse effects limit therapy with oral corticosteroids and ibuprofen. Azithromycin appears to be safe and effective, and is thus the most promising anti-inflammatory therapy available for patients with CF. Pharmacologic therapy with anti-inflammatory agents should be started early in the disease course, before extensive irreversible lung damage has occurred. To optimize anti-inflammatory therapy, it is necessary to understand the mechanism of action of these agents in the CF lung, to determine which of these agents would provide the most benefit to patients with CF, and to determine which therapies should be initiated at what age or stage of lung disease.
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References
Zuelzer WW, Newton Jr WA. The pathogenesis of fibrocystic disease of the pancreas: a study of 36 cases with special reference to the pulmonary lesions. Pediatrics 1949; 4(1): 53–69
Kirchner KK, Wagener JS, Khan TZ, et al. Increased DNA levels in bronchoalveolar lavage fluid obtained from infants with cystic fibrosis. Am J Respir Crit Care Med 1996; 154(5): 1426–9
Konstan MW, Hilliard KA, Norvell TM, et al., Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med 1994; 150(2): 448–54
Armstrong DS, Grimwood K, Carlin JB, et al. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997; 156 (4 Pt 1): 1197–204
Sagel SD, Kapsner R, Osberg I, et al. Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. Am J Respir Crit Care Med 2001; 164(1): 1425–31
Rosenfeld M, Gibson RL, McNamara S, et al. Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis. Pediatr Pulmonol 2001; 32(5): 356–66
Bonfield TL, Panuska JR, Konstan MW, et al. Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med 1995; 152 (6 Pt 1): 2111–8
Dechecchi MC, Nicolis E, Norez C, et al. Anti-inflammatory effect of miglustat in bronchial epithelial cells. J Cyst Fibros 2008; 7(6): 555–65
Balough K, McCubbin M, Weinberger M, et al. The relationship between infection and inflammation in the early stages of lung disease from cystic fibrosis. Pediatr Pulmonol 1995; 20(2): 63–70
Konstan MW, Berger M. Current understanding of the inflammatory process in cystic fibrosis: onset and etiology. Pediatr Pulmonol 1997; 24(2): 137–42; discussion 159-61
Doring G, Worlitzsch D. Inflammation in cystic fibrosis and its management. Paediatr Respir Rev 2000; 1(2): 101–6
Khan TZ, Wagener JS, Bost T, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995; 151(4): 1075–82
Macfarlane M, Leavy A, McCaughan J, et al. Successful decolonization of methicillin-resistant Staphylococcus aureus in paediatric patients with cystic fibrosis (CF) using a three-step protocol. J Hosp Infect 2007; 65(3): 231–6
Worlitzsch D, Herberth G, Ulrich M, et al. Catalase, myeloperoxidase and hydrogen peroxide in cystic fibrosis. Eur Respir J 1998; 11(2): 377–83
Dudez TS, Chanson M, Schlegel-Haueter SE, et al. Characterization ofa novel chemotactic factor for neutrophils in the bronchial secretions of patients with cystic fibrosis. J Infect Dis 2002; 186(6): 774–81
Douglas TA, Brennan S, Gard S, et al. Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis. Eur Respir J 2009; 33(2): 305–11
Doring G. Cystic fibrosis respiratory infections: interactions between bacteria and host defence. Monaldi Arch Chest Dis 1997; 52(4): 363–6
Armstrong DS, Hook SM, Jamsen KM, et al., Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr Pulmonol 2005; 40(6): 500–10
Doring G, Hoiby N. Early intervention and prevention of lung disease in cystic fibrosis: a European consensus. J Cyst Fibros 2004; 3(2): 67–91
Koyama S, Sato E, Nomura H, et al. The potential ofvarious lipopolysaccharides to release IL-8 and G-CSF. Am J Physiol Lung Cell Mol Physiol 2000; 278(4): L658–66
Jaffe A, Francis J, Rosenthal M, et al. Long-term azithromycin may improve lung function in children with cystic fibrosis [letter]. Lancet 1998; 351(9100): 420
Saiman L, Siegel J. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Infect Control Hosp Epidemiol 2003; 24(5): 1–93
Southern KW, Barker PM, Solis A. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2004; (2): CD002203
Hansen CR, Pressler T, Koch C, et al. Long-term azitromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study. J Cyst Fibros 2005; 4(1): 35–40
Clement A, Tamalet A, Leroux E, et al. Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial. Thorax 2006; 61(10): 895–902
Molinari G, Guzman CA, Pesce A, et al. Inhibition of Pseudomonas aeruginosa virulence factors by subinhibitory concentrations of azithromycin and other macrolide antibiotics. J Antimicrob Chemother 1993; 31(5): 681–8
Hoffmann N, Lee B, Hentzer M, et al. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice. Antimicrob Agents Chemother 2007; 51(10): 3677–87
Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000; 292(1): 156–63
Amsden GW. Anti-inflammatory effects of macrolides: an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother 2005; 55(1): 10–21
Tsai WC, Hershenson MB, Zhou Y, et al. Azithromycin increases survival and reduces lung inflammation in cystic fibrosis mice. Inflamm Res 2009; 58(8): 491–501
Takeshita K, Yamagishi I, Harada M, et al. Immunological and anti-inflammatory effects of clarithromycin: inhibition of interleukin 1 production of murine peritoneal macrophages. Drugs Exp Clin Res 1989; 15(11–12): 527–33
Cystic Fibrosis Foundation. Patient registry: annual data report 2008. Bethesda (MD): Cystic Fibrosis Foundation, 2008
Auerbach H, Kirkpatrick J, Williams M, et al. Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 1985; 326(8457): 686–8
Eggleston PA, Rosenstein BJ, Stackhouse CM, et al. A controlled trial of long-term bronchodilator therapy in cystic fibrosis. Chest 1991; 99(5): 1088–92
Dovey M, Aitken ML, Emerson J, et al. Oral corticosteroid therapy in cystic fibrosis patients hospitalized for pulmonary exacerbation: a pilot study. Chest 2007; 132(4): 1212–8
Bisgaard H, Pedersen SS, Nielsen KG, et al. Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Psuedomonas aeruginosa infection. Am J Respir Crit Care Med 1997; 156 (4 Pt 1): 1190–6
Ren CL, Pasta DJ, Rasouliyan L, et al. Relationship between inhaled corticosteroid therapy and rate of lung function decline in children with cystic fibrosis. J Pediatr 2008; 153(6): 746–51
Balfour-Lynn IM, Lees B, Hall P, et al. Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med 2006; 173(12): 1356–62
Balfour-Lynn IM, Welch K. Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst Rev 2009; (1): CD001915
Ross KR, Chmiel JF, Konstan MW. The role of inhaled corticosteroids in the management of cystic fibrosis. Paediatr Drugs 2009; 11(2): 101–13
Guran T, Ersu R, Karadag B, et al. Withdrawal of inhaled steroids in children with non-cystic fibrosis bronchiectasis. J Clin Pharm Ther 2008; 33(6): 603–11
Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995; 332(13): 848–54
Lands LC, Milner R, Cantin AM, et al. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr 2007; 151(3): 249–54
Konstan MW, Schluchter MD, Xue W, et al. Clinical use of ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med 2007; 176(11): 1084–9
Rosenstein B, Eigen H. Risks ofalternate-day prednisone in patients with cystic fibrosis. Pediatrics 1991; 87(2): 245–6
Dezateux C, Walters S, Balfour-Lynn I. Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst Rev 2000; (2): CD001915
Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis. Cochrane Database Syst Rev 2007; (4): CD001505
Chernick W. Comparison of tracheobronchial secretion in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics 1959; 24: 739–45
Smith AL, Redding G, Doershuk C, et al. Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis. J Pediatr 1988; 112(4): 547–54
Koch C, Høxiby N. Pathogenesis of cystic fibrosis. Lancet 1993; 341(8852): 1065–9
Houtmeyers E, Gosselink R, Gayan-Ramirez G, et al. Effects of drugs on mucus clearance. Eur Respir J 1999; 14(2): 452–67
Ratjen F, Paul K, van Koningsbruggen S, et al. DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha. Pediatr Pulmonol 2005; 39(1): 1–4
Shah PL, Scott SF, Knight RA, et al. The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis. Eur Respir J 1996; 9(3): 531–4
Paul K, Rietschel E, Ballmann M, et al. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med 2004; 169(6): 719–25
Costello CM, O’Connor CM, Finlay GA, et al. Effect of nebulised recombinant DNase on neutrophil elastase load in cystic fibrosis. Thorax 1996; 51(6): 619–23
Rochat T, Pastore FD, Schlegel_Haueter SE, et al. Aerosolized rhDNase in cystic fibrosis: effect on leucocyte proteases in sputum. Eur Respir J 1996; 9(11): 2200–6
McGrath LT, Mallon P, Dowey L, et al. Oxidative stress during acute respiratory exacerbations in cystic fibrosis. Thorax 1999; 54(6): 518–23
Ciofu O, Riis B, Pressler T, et al. Occurrence of hypermutable Pseudomonas aeruginosa in cystic fibrosis patients is associated with the oxidative stress caused by chronic lung inflammation. Antimicrob Agents Chemother 2005; 49(6): 2276–82
Gao L, Kim KJ, Yankaskas JR, et al. Abnormal glutathione transport in cystic fibrosis airway epithelia. Am J Physiol 1999; 277 (1 Pt 1): L113–8
van der Vliet A, Eiserich JP, Marelich GP, et al. Oxidative stress in cystic fibrosis: does it occur and does it matter? Adv Pharmacol 1997; 38: 491–513
Rahman I, Kelly F. Biomarkers in breath condensate: a promising new non-invasive technique in free radical research. Free Radic Res 2003; 37(12): 1253–66
Roum JH, Borok Z, McElvaney NG, et al. Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis. J Appl Physiol 1999; 87(1): 438–43
Morcillo EJ, Estrela J, Cortijo J. Oxidative stress and pulmonary inflammation: pharmacological intervention with antioxidants. Pharmacol Res 1999; 40(5): 393–404
Haddad JJ. Glutathione depletion is associated with augmenting a pro-inflammatory signal: evidence for an antioxidant/pro-oxidant mechanism regulating cytokines in the alveolar epithelium. Cytokines Cell Mol Ther 2000; 6(4): 177–87
Gao L, Broughman JR, Iwamoto T, et al. Synthetic chloride channel restores glutathione secretion in cystic fibrosis airway epithelia. Am J Physiol Lung Cell Mol Physiol 2001; 281(1): L24–30
Hudson VM. New insights into the pathogenesis of cystic fibrosis: pivotal role of glutathione system dysfunction and implications for therapy. Treat Respir Med 2004; 3(6): 353–63
Griese M, Ramakers J, Krasselt A, et al. Improvement of alveolar glutathione and lung function but not oxidative state in cystic fibrosis. Am J Respir Crit Care Med 2004; 169(7): 822–8
Bishop C, Hudson VM, Hilton SC, et al. A pilot study of the effect of inhaled buffered reduced glutathione on the clinical status of patients with cystic fibrosis. Chest 2005; 127(1): 308–17
Hartl D, Starosta V, Maier K, et al. Inhaled glutathione decreases PGE2 and increases lymphocytes in cystic fibrosis lungs. Free Radic Biol Med 2005; 39(4): 463–72
Tirouvanziam R, Conrad CK, Bottiglieri T, et al. High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci U S A 2006; 103(12): 4628–33
Visca A, Bishop CT, Hilton SC, et al. Improvement in clinical markers in CF patients using a reduced glutathione regimen: an uncontrolled, observational study. J Cyst Fibros 2008; 7(5): 433–6
Lee TW, Brownlee KG, Conway SP, et al. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros 2003; 2(1): 29–34
Cantin AM. Potential for antioxidant therapy of cystic fibrosis. Curr Opin Pulm Med 2004; 10(6): 531–6
Doring G, Goldstein W, Botzenhart K, et al. Elastase from polymorphonuclear leucocytes: a regulatory enzyme in immune complex disease. Clin Exp Immunol 1986; 64(3): 597–605
Doring G. Polymorphonuclear leukocyte elastase: its effects on the pathogenesis of Pseudomonas aeruginosa infection in cystic fibrosis. Antibiot Chemother 1989; 42: 169–76
Richman-Eisenstat JB, Jorens PG, Hebert CA, et al. Interleukin-8: an important chemoattractant in sputum of patients with chronic inflammatory airway diseases. Am J Physiol 1993; 264 (4 Pt 1): L413–8
Hartl D, Latzin P, Hordijk P, et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med 2007; 13(12): 1423–30
Doring G. The role of neutrophil elastase in chronic inflammation. Am J Respir Crit Care Med 1994; 150 (6 Pt 2): S114–7
Doring G, Frank F, Boudier C, et al. Cleavage of lymphocyte surface antigens CD2, CD4, and CD8 by polymorphonuclear leukocyte elastase and cathepsin G in patients with cystic fibrosis. J Immunol 1995; 154(9): 4842–50
O’Connor CM, Gaffney K, Keane J, et al. Alpha 1-proteinase inhibitor, elastase activity, and lung disease severity in cystic fibrosis. Am Rev Respir Dis 1993; 148 (6 Pt 1): 1665–70
Birrer P, McElvaney NG, Rudeberg A, et al. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med 1994; 150(1): 207–13
Hubbard R, McElvaney NG, Birrer P, et al. A preliminary study of aerosolised recombinant human deoxyribonuclease in treatment of cystic fibrosis. N Engl J Med 1992; 326: 812–5
Birrer P. Proteases and antiproteases in cystic fibrosis: pathogenetic considerations and therapeutic strategies. Respiration 1995; 62Suppl. 1: 25–8
Moraes TJ, Plumb J, Martin R, et al. Abnormalities in the pulmonary innate immune system in cystic fibrosis. Am J Respir Cell Mol Biol 2006; 34(3): 364–74
Griese M, Kappler M, Gaggar A, et al. Inhibition of airway proteases in cystic fibrosis lung disease. Eur Respir J 2008; 32(3): 783–95
Doring G, Elborn JS, Johannesson M, et al. Clinical trials in cystic fibrosis. J Cyst Fibros 2007; 6(2): 85–99
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Pressler, T. Targeting Airway Inflammation in Cystic Fibrosis in Children. Pediatr-Drugs 13, 141–147 (2011). https://doi.org/10.2165/11588150-000000000-00000
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DOI: https://doi.org/10.2165/11588150-000000000-00000