Cystic Fibrosis and Pseudomonas
PKGhatak, MD
Cystic fibrosis (CF) is an inherited disease due to gene mutation and is transmitted by autosomal recessive mode.
Cystic Fibrosis is due to a mutation in the Transmembrane conductance regulator gene (CFTR) on chromosome 7. The CFTR gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as a channel for chloride ion transport across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. In addition to the CFTR gene, another 1,700 gene mutations are associated with CF.In normal circumstances, the proper hydration of the surface layer and the viscosity of mucus secreted by the Goblet cells of the respiratory tract are maintained by keeping the electrolyte concentration constant. The movement of sodium ions across the cells is maintained by ATP derived active sodium channels. In Cystic Fibrosis, the Sodium channel is normal. Due to defective CFTR protein, the conductance regulator of the chloride channel and calcium activated chloride channel fail. Chloride ions are not absorbed back into the cells from the surrounding water layer. Sodium concentration also increases in the fluid secondarily in maintaining the balance of cations and anions. In a recent study, the CFTR gene mutation is identified in the cilia. The abnormal motility of cilia is due to thick, sticky mucus and not in the ciliary protein that moves the cilia.
A thin layer of low viscosity fluid separates the ciliary epithelium from a 5 micron thick mucus layer of the respiratory tract and functions as a lubricant for ciliary movement. Maintenance of normal concentrations of sodium and chloride and the resultant osmolarity of this fluid layer is essential for the coordinated ciliary movement that propels the mucus toward the vocal cord for elimination from the airways.
Patients homozygous for the abnormal CF genes show defective ciliary movement due to the high concentration of Na + Cl ions in the surrounding fluid. This abnormality leads to thick mucus accumulation in the respiratory tract, pancreas, liver, intestine and reproductive ducts. The degree of severity of the clinical states varies. CF newborns are likely to be born preterm, have a lower birth weight, lower life expectancy and occasionally a life threatening condition called meconium ileus. Most CF cases are diagnosed in early childhood, but occasional young adults present with chronic cough, recurrent sinusitis and failure to gain weight.
All newborns are required to have state mandated genetic tests on the heel blood obtained at the time of birth. Those newborns with positive genetic screening tests are followed by the Sweat Chloride test. If chloride levels are high - the diagnosis of CF is confirmed.
People carriers of one copy of the mutated CFTR gene are slightly more susceptible to URI, sinusitis, bronchiectasis and pancreatic cancer.
What is the relation of sweat chloride to the ciliary motility of respiratory epithelium.
In CF, the chloride ion fails to be absorbed back into the cells from the surrounding hyperosmolar fluid and water from the cells moves out, leading to the dehydration of cells. As sodium chloride concentration also increases in the fluid, the fluid viscosity increases and ciliary movement becomes disorganized and ineffective to propel mucus upward along the mucociliary escalator for clearing. If bacteria, like Pseudomonas aeruginosa, find their way into the lungs, then Pseudomonas bacteria can stay in contact with the epithelium longer and have time to attach themselves and invade the tissues. And inflammation begins. As the process becomes frequent, the pseudomonas change from being swimmers to swarmers. The biofilms they produce help them to coalesce together tighter and resist beta-lactamase antibiotics and then Pseudomonas become resistant to beta-lactamase antibiotics.
Pseudomonas.
Pseudomonas is a gram negative rod shaped, encapsulated organism. It is present ubiquitously in the soil, water, man-made materials including hospital equipment, catheters and ventilators. In culture media, it produces surface growth and produces various shades of green color, and emits a tortilla-like odor. It is aerobic bacteria but also a facultative anaerobe. It has a flagellum at one end and is a free swimmer. The colony can form biofilms that become resistant to antibiotics. The bacteria produce exotoxin A, which can inhibit protein synthesis in the immunocytes and immunocytes die as a consequence. The organism produces catalase, oxidase and citrate.
Pseudomonas aeruginosa is phagocytized in the early stage of infection. But Pseudomonas survives in the phagocytes by blocking the digestive enzymes of phagocytes. It also neutralizes IL1 beta and caspase1 as a result of the inflammation and control of the spread of infection becomes inadequate. In repeated infections, the Pseudomonas form biofilms and the colony becomes compact. And Pseudomonas changes from being free swimmers to swarmers. A subunit of the FilC protein of the flagellar protein flagellin is a chloride sensor, mutate. In CF, the Pseudomonas mutation of the FilC gene makes Pseudomonas grow more aggressively in the high chloride environment.
Cystic fibrosis, a debilitating and difficult to treat, inherited disease. Chloride ion transport disorder results in thick sticky mucus in the respiratory tract that is an opportunity for pseudomonas to colonize and then infect the lungs and cause repeated bouts of pneumonia. Pseudomonas aeruginosa thrives inside the macrophages, kills Immunocytes and neutralizes inflammatory response and inherently develops resistance to antibiotics.
This is a rare lethal combination for people suffering from CF.
In every community, the Cystic Fibrosis Foundation and the American Lung Association provide support, updated information and assistance in varieties of ways to help unfortunate sufferers and their families.
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