Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CFTR, or cystic fibrosis transmembrane conductance regulator, the gene product that is defective in cystic fibrosis, is present in the apical membrane of the epithelial cells from the stomach to the colon. In the foregut, the clinical manifestations are not directly related to the primary defect of the CFTR chloride channel. The most troublesome complaints and symptoms originate from the oesophagus as peptic oesophagitis or oesophageal varices. In the small intestinal wall, the clinical expression of CF depends largely on the decreased secretion of fluid and chloride ions, the increased permeability of the paracellular space between adjacent enterocytes and the sticky mucous cover over the enterocytes. As a rule, the brush border enzyme activities are normal and there is some enhanced active transport as shown for glucose and alanine. The results of continuous enteral feeding of CF patients clearly show that the small intestinal mucosa, in the daily situation, is not functioning at maximal capacity. Although CFTR expression in the colon is lower, the large intestine may be the site of several serious complications such as rectal prolapse, meconium ileus equivalent, intussusception, volvulus and silent appendicitis. In recent years colonic strictures, after the use of high-dose pancreatic enzymes, are being increasingly reported; the condition has recently been called CF fibrosing colonopathy. The CF gastrointestinal content itself differs mainly from the normal condition by the lower acidity in the foregut and the accretion of mucins and proteins, eventually resulting in intestinal obstruction, in the ileum and colon. Better understanding of the CF gastrointestinal phenotype may contribute to improvement of the overall wellbeing of these patients.
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PMID:Gastrointestinal manifestations in cystic fibrosis. 886 67

One of the main functions of the airway epithelium is to inactivate and remove infectious particles from inhaled air and thereby prevent infection of the distal lung. This function is achieved by mucociliary and cough clearance and by antimicrobial factors present in the airway surface liquid (ASL). There are indications that airway defenses are affected by the pH of the ASL and historically, acidification of the airway surfaces has been suggested as a measure of airway disease. However, even in health, the ASL is slightly acidic, and this acidity might be part of normal airway defense. Only recently research has focused on the mechanisms responsible for acid and base secretion into the ASL. Advances resulted from research into the airway disease associated with cystic fibrosis (CF) after it was found that the CFTR Cl(-) channel conducts HCO (3) (-) and, therefore, may contribute to ASL pH. However, the acidity of the ASL indicated parallel mechanisms for H(+) secretion. Recent investigations identified several H(+) transporters in the apical membrane of the airway epithelium. These include H(+) channels and ATP-driven H(+) pumps, including a non-gastric isoform of the H(+)-K(+) ATPase and a vacuolar-type H(+) ATPase. Current knowledge of acid and base transporters and their potential roles in airway mucosal pH regulation is reviewed here.
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PMID:Mechanisms of acid and base secretion by the airway epithelium. 1709 Dec 14

The properties of the voltage-dependent H(+) channel have been studied in lung epithelial cells for many years, and recently HVCN1 mRNA expression has been linked directly to H(+) channel function in lung epithelium. The H(+) channel is activated by strong membrane depolarization, intracellular acidity, or extracellular alkalinity. Early on it was noted that these are surprising physiological channel characteristics when considering that lung epithelial cells have rather stable membrane potentials and a well pH-buffered intracellular milieu. This raised the question under which conditions the H(+) channel is active in lung epithelium and what is its physiological function there. Current understanding of the HVCN1 H(+) channel in lung epithelial acid secretion, its activation by an alkaline mucosal extracellular pH, and its role in the regulation of the mucosal pH of the lung has resulted in a model of mucosal pH regulation based on the parallel function of the HVCN1 H(+) channel and the CFTR HCO(3) (-) channel, which suggests that HVCN1 is a critical factor that maintains a neutral surface pH in the lung.
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PMID:Function of Proton Channels in Lung Epithelia. 2266 11

Healthful cell maintenance requires the efficient degradative processing and removal of waste material. Retinal pigmented epithelial (RPE) cells have the onerous task of degrading both internal cellular debris generated through autophagy as well as phagocytosed photoreceptor outer segments. We propose that the inadequate processing material with the resulting accumulation of cellular waste contributes to the downstream pathologies characterized as age-related macular degeneration (AMD). The lysosomal enzymes responsible for clearance function optimally over a narrow range of acidic pH values; elevation of lysosomal pH by compounds like chloroquine or A2E can impair degradative enzyme activity and lead to a lipofuscin-like autofluorescence. Restoring acidity to the lysosomes of RPE cells can enhance activity of multiple degradative enzymes and is therefore a logical target in early AMD. We have identified several approaches to reacidify lysosomes of compromised RPE cells; stimulation of beta-adrenergic, A2A adenosine and D5 dopamine receptors each lowers lysosomal pH and improves degradation of outer segments. Activation of the CFTR chloride channel also reacidifies lysosomes and increases degradation. These approaches also restore the lysosomal pH of RPE cells from aged ABCA4(-/-) mice with chronically high levels of A2E, suggesting that functional signaling pathways to reacidify lysosomes are retained in aged cells like those in patients with AMD. Acidic nanoparticles transported to RPE lysosomes also lower pH and improve degradation of outer segments. In summary, the ability of diverse approaches to lower lysosomal pH and enhance outer segment degradation support the proposal that lysosomal acidification can prevent the accumulation of lipofuscin-like material in RPE cells.
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PMID:Rescue of compromised lysosomes enhances degradation of photoreceptor outer segments and reduces lipofuscin-like autofluorescence in retinal pigmented epithelial cells. 2466 87

Cystic fibrosis (CF) is a common, life-threatening, multisystemic, autosomal recessive disorder. In the last few years, giant steps have been made with regard to the understanding of CF pathophysiology, allowing the scientific community to propose mechanisms that cause the myriad of CF clinical manifestations. Following the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, the structure and function of the CFTR protein were described. Since then, more than 2,000 variants of the CFTR gene and their impact on the amount and function of the CFTR protein have been reported. The role of the CFTR protein as an ion channel transporting chloride and bicarbonate and its repercussions on different epithelial cell-lined organs and mucus are now better understood. Mechanisms behind susceptibility to infection in CF have also been proposed and include abnormalities in the composition, volume and acidity of the airway surface liquid, changes in the submucosal gland's anatomy and function, and deficiencies in the mucociliary clearance system. Numerous hypotheses explaining the excessive inflammatory response in CF are also debated and involve impaired mucociliary clearance, persistent hypoxia, lipid abnormalities, protease and antiprotease disproportion, and oxidant and antioxidant imbalance. The purpose of this review is to summarize our current knowledge of CF pathophysiology, including significant historic discoveries and most recent breakthroughs, and to improve understanding and awareness of this fatal disease.
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PMID:Cystic Fibrosis: Pathophysiology of Lung Disease. 3165 25