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. 2015 Jan 22;372(4):351-62.
doi: 10.1056/NEJMra1300109.

Origins of Cystic Fibrosis Lung Disease

Free PMC article

Origins of Cystic Fibrosis Lung Disease

David A Stoltz et al. N Engl J Med. .
Free PMC article


Figure 1
Figure 1. Early Cystic Fibrosis Airway Disease in Humans and Pigs
Histological images from the lungs of a cystic fibrosis infant (Panel A, 3 months age) and a cystic fibrosis pig (Panel B, 2 months age). Airways-centric neutrophilic inflammation (arrows) obstructs airway lumens. Sections stained with hematoxylin and eosin.
Figure 2
Figure 2. Structural Airway Abnormalities in Cystic Fibrosis
Panel A shows three-dimensional reconstructions from micro-computed tomography images of the laryngeal and upper tracheal region of non-cystic fibrosis (non-CF) and cystic fibrosis (CF) mice (6-8 weeks old). Cartilage ring structure (yellow) is disrupted, and the tracheal lumen (gray) is narrowed in cystic fibrosis mice. Panel B shows three-dimensional reconstructions from optical coherence tomography (OCT) images of tracheal cartilage rings in non-cystic fibrosis and cystic fibrosis newborn pigs. Individual cartilage rings are highlighted by different colors. Panel C shows three-dimensional reconstructions from computed tomography images of ethmoid (red) and maxillary (green) sinuses in newborn non-cystic fibrosis and cystic fibrosis pigs. Cystic fibrosis pigs have hypoplastic ethmoid sinuses. Panel D shows chest CT image of a cystic fibrosis piglet on the day of birth and before airway infection, inflammation, and mucus obstruction. Air trapping (red arrows), a sign of airway obstruction, is already present. For comparison, Panel E shows air trapping on chest CT image from a 14-month-old human with cystic fibrosis. Murine tracheas were provided by Drs. Craig Hodges and Mitch Drumm (Case Western Reserve University) and analyzed by Ryan Adam (University of Iowa). OCT image acquisition and analysis were performed by Drs. Melissa Suter (Massachusetts General Hospital) and Eman Namati (University of Iowa). Sinus image analysis was performed by Dr. Eugene Chang and Tanner Wallen (University of Iowa).
Figure 3
Figure 3. Host Defense Defects in Newborn Cystic Fibrosis Pigs
Panel A. At birth, newborn cystic fibrosis (CF) pigs have a more acidic airway surface liquid pH, than non-cystic fibrosis (non-CF) littermates. Panel B. Airway surface liquid in newborn non-cystic fibrosis piglets quickly killed most S. aureus applied to the airway surface. In contrast, killing was reduced by about half in cystic fibrosis piglets. Each set of connected points represents data from an individual piglet. Panel C. Increasing airway surface liquid pH by aerosolizing sodium bicarbonate (NaHCO3) onto airways of cystic fibrosis piglets rescued the cystic fibrosis bacterial killing defect, compared to treatment with saline (NaCl) alone. Panels A-C are from Pezzulo et al. . Panel D. Images from a computed-tomography based assay of mucociliary transport that tracked radio-opaque microdisks. Images are three-dimensional reconstructions of the airway tree from newborn non-cystic fibrosis and cystic fibrosis piglets taken at the beginning and end of the tracking period (10 min duration). Positions of microdisks are represented by black circles (larger than actual microdisks). Following in vivo cholinergic stimulation to stimulate mucus secretion from submucosal glands, most microdisks cleared the airway tree in non-cystic fibrosis piglets. In cystic fibrosis piglets, some microdisks move normally, but some became stuck and failed to clear the viewing field. Panel D is from Hoegger et al. . Panel E. Mucus strands were visualized with fluorescent nanospheres that bound to mucus in excised tracheas submerged in saline. Tracheas were studied ex vivo following in vivo cholinergic stimulation. In non-cystic fibrosis tracheas, most of the mucus (green) accumulated around the tracheal edges, and very few mucus strands were observed. In contrast, in cystic fibrosis tracheas, numerous mucus strands failed to detach from submucosal gland ducts. These tethered mucus strands contribute to impaired mucociliary transport.
Figure 4
Figure 4. Accumulation of Mucus in Humans with Cystic Fibrosis and Animal Models of Cystic Fibrosis
Panels A-E. “Stringy” appearance of mucus arising from glands. Mucus secreted from submucosal glands in pulmonary airways remained in the gland duct in a 7-month-old baby with cystic fibrosis (A), a 2-month-old cystic fibrosis pig (B), and an 8-month-old cystic fibrosis ferret (C). Mucus also emerged from submucosal glands in ethmoid sinus olfactory epithelium that did not contain goblet cells (D, 1-month-old cystic fibrosis pig). Similar to mucus from submucosal glands, mucus arising from colonic crypts of newborn cystic fibrosis pigs can show a stringy appearance and adherence to the site of origin (E, newborn cystic fibrosis pig). Panels F-I. Lamellar appearance of mucus along epithelia. In affected intrapulmonary airways, mucus can have a lamellar appearance lying along airway walls (F, 2-month-old cystic fibrosis pig). A similar pattern of mucus arising from goblet cells can occur in ethmoid sinuses where respiratory epithelium lacks submucosal glands, and mucus can sometimes be traced back to the cells of origin (G, 1-month-old cystic fibrosis pig). Likewise, mucus can have a lamellar appearance and be traced back to the cell of origin in microgallbladder (H, newborn cystic fibrosis pig). Pancreatic ducts also can show obstruction by mucus (I, 6-month-old cystic fibrosis pig). The authors thank Drs. Marcus Nashelsky, and Morris Dailey (University of Iowa, Department of Pathology) for assistance with archival autopsy data.
Figure 5
Figure 5. Model of Cystic Fibrosis Airway Host Defense Defects.
Panel A. Cystic fibrosis (CF) airways exhibit two host defense defects at the genesis of the disease. On the left, loss of CFTR channels that conduct chloride (Cl) and bicarbonate (HCO3) onto the airway surface causes the airway surface liquid pH to fall, and the acidic airway surface liquid inhibits the activity of antimicrobials. On the right, loss of CFTR channels in submucosal glands causes mucus to develop abnormal properties so that it does not break free after emerging and remains tethered to the gland ducts. Panel B. When bacteria enter non-cystic fibrosis airways (top) they are killed by airway surface liquid antimicrobials, mucociliary transport sweeps them out of the lung, and other defenses including phagocytic cells eradicate them to maintain sterile lungs. In cystic fibrosis (bottom) antimicrobial activity and mucociliary transport are less effective than in non-cystic fibrosis and other defenses may also be impaired. Eventually, the host defenses are overwhelmed, and bacteria proliferate, with inflammation, remodeling, immunity, and genetic changes in the bacteria influencing the species that will dominate. In addition, the resulting inflammation and airway remodeling may further enhance or impair host defense mechanisms. Airway insults will also affect host defenses. The authors thank Dr. Mahmoud Abou Alaiwa and Mr. Shawn Roach for assistance with graphics.

Comment in

  • Origins of cystic fibrosis lung disease.
    Stoltz DA, Meyerholz DK, Welsh MJ. Stoltz DA, et al. N Engl J Med. 2015 Apr 16;372(16):1574-5. doi: 10.1056/NEJMc1502191. N Engl J Med. 2015. PMID: 25875271 No abstract available.
  • Origins of cystic fibrosis lung disease.
    Munder A, Tümmler B. Munder A, et al. N Engl J Med. 2015 Apr 16;372(16):1574. doi: 10.1056/NEJMc1502191. N Engl J Med. 2015. PMID: 25875272 No abstract available.

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