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Ion transport across the jejunum in normal and cystic fibrosis mice
1Department of Medicine, University of North Carolina at Chapel Hill 27599-7020.
Abstract:
Cystic fibrosis (CF) mice created by targeted disruption of the murine cystic fibrosis transmembrane conductance regulator gene lack adenosine 3',5'-cyclic monophosphate (cAMP)-mediated Cl- secretion and exhibit marked intestinal complications secondary to inadequate fluid secretion. The basal short-circuit current (Isc) in the normal murine jejuna [43.2 +/- 5.9 microA.cm-2, n = 10 (mean +/- SE)] exhibits marked spontaneous n = 10 (mean +/- SE)] exhibits marked spontaneous oscillations (amplitude = 47.9 microA.cm-2, n = 18), which were completely absent in the CF jejunum. Treatment of normal jejuna with the neuronal blocker tetrodotoxin completely eliminated the oscillations and decreased the Isc to levels not significantly different from the low basal Isc (5.4 +/- 2.8 microA.cm-2, n = 16) exhibited by CF tissue. Ion substitution studies revealed basal Isc in normal jejuna to be due primarily to Cl- secretion but these tissues appeared to be capable of HCO3- secretion as well. In contrast, CF jejuna spontaneously secreted neither Cl- nor HCO3-, which may indicate that CF jejuna have a defect in the ability to secrete both of these anions. Apical glucose elicited an electrogenic absorption of Na+ of identical magnitude in normal and CF jejuna. Without apical glucose, CF jejuna exhibited a very small Isc response to forskolin (delta 2.2 +/- 0.67 microA.cm-2, n = 10). However, in the presence of apical glucose, forskolin elicited an eightfold greater Isc response in the CF tissue (delta 17.2 +/- 4.8 microA.cm-2, n = 9).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Cystic fibrosis (CF) mice exhibit intestinal complications due to defective anion secretion. Restoring fluid secretion with glucose partially rescues cAMP-mediated responses in CF jejunum, suggesting a potential therapeutic target.
Area of Science:
- Physiology
- Gastroenterology
- Genetics
Background:
- Cystic fibrosis (CF) is a genetic disorder affecting fluid secretion.
- CF mice models exhibit intestinal issues due to impaired ion transport.
- Adenosine 3',5'-cyclic monophosphate (cAMP)-mediated chloride (Cl-) secretion is crucial for intestinal fluid balance.
Purpose of the Study:
- To investigate ion secretion defects in the jejunum of CF mice.
- To understand the role of neuronal signaling and anion secretion in CF intestinal complications.
- To explore the potential of glucose to modulate cAMP-mediated responses in CF jejunum.
Main Methods:
- Utilized cystic fibrosis transmembrane conductance regulator (CFTR) gene-disrupted mice.
- Measured short-circuit current (Isc) in jejunal tissues.
- Employed ion substitution, tetrodotoxin, and forskolin treatments.
- Assessed responses to apical glucose.
Main Results:
- Normal murine jejuna showed spontaneous oscillations in Isc, absent in CF jejuna.
- Neuronal blockade abolished oscillations and reduced Isc in normal tissue.
- CF jejuna failed to secrete Cl- or bicarbonate (HCO3-).
- Glucose enhanced forskolin-induced Isc in CF jejuna significantly.
Conclusions:
- CF jejuna exhibit defects in both Cl- and HCO3- secretion.
- Neuronal activity contributes to basal Isc in normal jejuna.
- Glucose enhances cAMP-mediated anion secretion in CF jejunum, indicating a potential therapeutic avenue.
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