title: Doxycycline improves clinical outcomes during cystic fibrosis exacerbations.
abstract: Matrix metalloprotease-9 (MMP-9) plays a role in progression of cystic fibrosis, and doxycycline can reduce MMP-9in vitroHere, we explore the effect of doxycycline during cystic fibrosis exacerbation treatment on MMP-9 related readouts and clinical end-points.This randomised, double-blind, placebo-controlled study enrolled hospitalised patients with cystic fibrosis undergoing exacerbation. In total, 20 participants were given doxycycline and 19 participants were given placebo over an 8-day period during hospitalisation. Biospecimens were collected at the beginning and the end of the study period. Primary end-points were total MMP-9 levels in the sputum and safety/tolerability. Secondary end-points included change in lung function, time to next exacerbation, and markers of MMP-9-related protease activity (active MMP-9 and TIMP-1). Nonparametric testing was used for within-group and between-group analyses.Doxycycline was well tolerated, with no treatment discontinuations or serious adverse events. Doxycycline reduced total sputum MMP-9 levels by 63.2% (p<0.05), and was also associated with a 56.5% reduction in active MMP-9 levels (p<0.05), a 1.6-fold increase in sputum TIMP-1 (p<0.05), improvement in forced expiratory volume in 1 s (p<0.05), and an increase in time to next exacerbation (p<0.01).Adjunctive use of doxycycline improved dysregulated MMP-9 levels in sputum, along with biomarkers consistent with a reduced proteolytic pulmonary environment. Improvement in clinical outcome measures suggests an important therapeutic benefit of doxycycline for individuals with cystic fibrosis.
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA.|Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.|Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Medical Service at Birmingham VA Medical Center, Birmingham, AL, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA.|Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Abdalla
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA.|Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Preston E
authors.initials: PE
authors.lastname: Bratcher
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA.|Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.|Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Medical Service at Birmingham VA Medical Center, Birmingham, AL, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.affiliation: Physician Assistant Studies Program, Christian Brothers University, Memphis, TN, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Sabbatini
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA.|Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.|Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Medical Service at Birmingham VA Medical Center, Birmingham, AL, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wells
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA.|Biostatistics Program, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Lou
authors.affiliation: Dept of Pharmacy, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Quinn
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA.|Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.|Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Dept of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.affiliation: Cincinnati Children's Hospital Medical Center and The University of Cincinnati, Cincinnati, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Clancy
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, USA agaggar@uabmc.edu.|Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.|Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, USA.|Medical Service at Birmingham VA Medical Center, Birmingham, AL, USA.|Dept of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
mesh_terms: D000293:Adolescent; D000328:Adult; D000407:Alabama; D003550:Cystic Fibrosis / Q000188:drug therapy*; D004311:Double-Blind Method; D004318:Doxycycline / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008168:Lung / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D013183:Sputum / Q000737:chemistry; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline