Using a unique animal model of CF, a team of scientists from the University of Iowa has discovered a surprising difference between healthy airways and airways affected by CF that leads to reduced bacterial killing in CF airways. The finding directly links the genetic cause of CF -- mutations in a channel protein called cystic fibrosis transmembrane conductance regulator (CFTR) -- to the disruption of a biological mechanism that protects lungs from bacterial infection.
The study, published in the July 5 issue of Nature, shows that the thin layer of liquid coating the airways is more acidic in newborn pigs with CF than in healthy newborn pigs, and that the increased acidity (lower pH) reduces the ability of the liquid to kill bacteria. Moreover, making the airway liquid less acidic with a simple solution of baking soda restores bacterial killing in CF airways to almost normal levels.
Although the findings suggest that therapies that raise the pH of the airway surface liquid (ASL) may help prevent infection in CF, the researchers strongly caution that this discovery is at an early stage.
"Some have asked us if people with CF should inhale an aerosol that would raise the pH of the ASL," says Joseph Zabner, M.D., UI professor of internal medicine and senior study author. "At this point, we have no idea if that would help. And more importantly, it could be harmful."
"This was a very surprising finding," adds Alejandro Pezzulo, M.D., UI postdoctoral fellow and co-lead author of the study. "There have been many ideas as to what goes wrong in CF, but lack of a good experimental model has made it difficult to gain insight into how the disease gets started."
Unlike mouse models of the disease, the CF pigs develop lung disease that closely mimics what is seen in humans. Previous studies from the UI lab showed that although the airways of CF pigs are infection-free at birth, they are less able to get rid of bacteria than healthy airways and quickly become infected.
Testing bacterial killing in airways
The UI team, including Pezzulo and co-lead author Xiao Xiao Tang, Ph.D., a Howard Hughes Medical Institute postdoctoral research associate at the UI, developed a simple experiment to study bacterial killing by the ASL. They immobilized bacteria on a tiny gold grid and exposed these bacteria to ASL from CF-affected and healthy pigs.
The ASL from normal airways killed most of the bacteria very rapidly, whereas the ASL from CF-affected airways only killed about half of the bacteria, suggesting that in CF airways some bacteria would survive and go on to cause infection.
Further investigation showed that although many characteristics of the ASL in CF and non-CF pigs are similar, the ASL from CF airways is more acidic than the liquid from healthy airways.
When the scientists raised the pH of the ASL in CF pigs through inhalation of a solution of sodium bicarbonate (baking soda), the treated ASL was capable of killing most of the bacteria on the grid (just like ASL from normal airways). Conversely, lowering the pH of ASL from normal airways reduced bacterial killing. The finding confirms that pH is a critical factor for bacterial killing,
"This study explains why a defect in the CFTR channel protein leads to reduced bacterial killing and an airway host defense defect," Tang says. "Impaired bicarbonate transport because of the defective CFTR could cause increased acidity in the ASL, which the study shows reduces the ASL bacterial killing capability."
Potential clinical applications
Although the approach is not ready for clinical application, the study indicates that pH is a contributing factor in airway infection, suggesting that therapies that modify airway pH may potentially be helpful in preventing infection in CF patients.
In addition, the researchers believe that using the bacteria-coated grids to measure bacterial killing in airways might provide a simple way to test the effectiveness of other new CF therapies that currently are being developed.
The UI team also included Mark Hoegger; Mahmoud Abou Alaiwa; Shyam Ramachandran; Thomas Moninger; Phillip Karp, Christine Wohlford-Lenane; Henk Haagsman; Martin van Eijk; Botond Banfi; Alexander Horsewill; David Stoltz; Paul McCray; and Michael Welsh.
The work was supported in part by grants from the National Heart, Lung, and Blood Institute (HL51670, HL091842, HL102288), and the Cystic Fibrosis Foundation. Welsh is a Howard Hughes Medical Institute (HHMI) investigator.
Jennifer Brown | EurekAlert!
Flavins keep a handy helper in their pocket
25.04.2018 | University of Freiburg
Complete skin regeneration system of fish unraveled
24.04.2018 | Tokyo Institute of Technology
At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.
Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...
Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.
Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
25.04.2018 | Physics and Astronomy
25.04.2018 | Physics and Astronomy
25.04.2018 | Information Technology