2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

      Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          <p class="first" id="d3415373e476"> <b>Rationale:</b> Classical interpretation of cystic fibrosis (CF) lung disease pathogenesis suggests that infection initiates disease progression, leading to an exuberant inflammatory response, excessive mucus, and ultimately bronchiectasis. Although symptomatic antibiotic treatment controls lung infections early in disease, lifelong bacterial residence typically ensues. Processes that control the establishment of persistent bacteria in the CF lung, and the contribution of noninfectious components to disease pathogenesis, are poorly understood. </p><p id="d3415373e481"> <b>Objectives:</b> To evaluate whether continuous antibiotic therapy protects the CF lung from disease using a ferret model that rapidly acquires lethal bacterial lung infections in the absence of antibiotics. </p><p id="d3415373e486"> <b>Methods:</b> <i>CFTR</i> (cystic fibrosis transmembrane conductance regulator)–knockout ferrets were treated with three antibiotics from birth to several years of age and lung disease was followed by quantitative computed tomography, BAL, and histopathology. Lung disease was compared with CFTR-knockout ferrets treated symptomatically with antibiotics. </p><p id="d3415373e494"> <b>Measurements and Main Results:</b> Bronchiectasis was quantified from computed tomography images. BAL was evaluated for cellular differential and features of inflammatory cellular activation, bacteria, fungi, and quantitative proteomics. Semiquantitative histopathology was compared across experimental groups. We demonstrate that lifelong antibiotics can protect the CF ferret lung from infections for several years. Surprisingly, CF animals still developed hallmarks of structural bronchiectasis, neutrophil-mediated inflammation, and mucus accumulation, despite the lack of infection. Quantitative proteomics of BAL from CF and non-CF pairs demonstrated a mucoinflammatory signature in the CF lung dominated by Muc5B and neutrophil chemoattractants and products. </p><p id="d3415373e499"> <b>Conclusions:</b> These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections. </p>

          Related collections

          Most cited references 37

          • Record: found
          • Abstract: not found
          • Article: not found

          Airway mucus function and dysfunction.

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective.

            The airways of patients with cystic fibrosis (CF) are nearly always infected with many different microorganisms. This environment offers warm, humid and nutrient-rich conditions, but is also stressful owing to frequent antibiotic therapy and the host immune response. Pseudomonas aeruginosa is commonly isolated from the airways of patients with CF, where it most often establishes chronic infections that usually persist for the rest of the lives of the patients. This bacterium is a major cause of mortality and morbidity and has therefore been studied intensely. Here, we discuss how P. aeruginosa evolves from a state of early, recurrent intermittent colonization of the airways of patients with CF to a chronic infection state, and how this process offers opportunities to study bacterial evolution in natural environments. We believe that such studies are valuable not only for our understanding of bacterial evolution but also for the future development of new therapeutic strategies to treat severe chronic infections.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Muc5b is required for airway defence.

              Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
                Bookmark

                Author and article information

                Journal
                American Journal of Respiratory and Critical Care Medicine
                Am J Respir Crit Care Med
                American Thoracic Society
                1073-449X
                1535-4970
                May 15 2018
                May 15 2018
                : 197
                : 10
                : 1308-1318
                Affiliations
                [1 ]Department of Anatomy &amp; Cell Biology
                [2 ]Department of Medicine
                [3 ]Department of Surgery
                [4 ]Department of Biomedical Engineering, College of Engineering, and
                [5 ]Proteomics Facility
                [6 ]Department of Radiology, and
                [7 ]Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa; and
                [8 ]Department of Pediatrics, University of Colorado, Aurora, Colorado
                [9 ]Department of Pathology, Carver College of Medicine
                Article
                10.1164/rccm.201708-1616OC
                5955060
                29327941
                © 2018

                Comments

                Comment on this article