Contrasting effects of linaclotide and lubiprostone on restitution of epithelial cell barrier properties and cellular homeostasis after exposure to cell stressors.

Cuppoletti J, Blikslager AT, Chakrabarti J, Nighot PK, Malinowska DH

BMC pharmacology3 May 2012Cited by 29 (Europe PMC)

PMID22553939PMCIDPMC3403872DOI10.1186/1471-2210-12-3PepBankPUB-22553939

Summary

BackgroundLinaclotide has been proposed as a treatment for the same gastrointestinal indications for which lubiprostone has been approved, chronic idiopathic constipation and irritable bowel syndrome with constipation. Stressors damage the epithelial cell barrier and cellular homeostasis leading to loss of these functions. Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined. Comparison with effects of lubiprostone, known to promote repair of barrier function was carried out.ResultsIn ischemia-damaged pig jejunum, using measurements of transepithelial resistance, (3)H-mannitol fluxes, short-circuit current (Cl(-) secretion) and occludin localization, active linaclotide failed to effectively promote repair of the epithelial barrier or recovery of short-circuit current, whereas lubiprostone promoted barrier repair and increased short-circuit current. In control pig jejunum, 1 μM linaclotide and 1 μM lubiprostone both caused similar increases in short-circuit current (Cl(-) secretion). In T84 cells, using measurements of transepithelial resistance, fluxes of fluorescent macromolecules, occludin and mitochondrial membrane potential, active linaclotide was virtually ineffective against damage caused by interferon-γ and tumor necrosis factor-α, while lubiprostone protected or promoted repair of epithelial barrier and cell function. Barrier protection/repair by lubiprostone was inhibited by methadone, a ClC-2 inhibitor. Linaclotide, but not lubiprostone increased [cGMP]i as expected and [Ca(2+)]i and linaclotide depolarized while lubiprostone hyperpolarized the T84 plasma membrane potential suggesting that lubiprostone may lead to greater cellular stability compared to linaclotide. In T84 cells, as found with linaclotide but not with lubiprostone, transepithelial resistance was slightly but significantly decreased by guanylin, STa and 8-bromo cGMP and fluorescent dextran fluxes were increased by guanylin. However the physiological implications of these small but statistically significant changes remain unclear.ConclusionsConsidering the physiological importance of epithelial barrier function and cell integrity and the known impact of stressors, the finding that lubiprostone, but not active linaclotide, exhibits the additional distinct property of effective protection or repair of the epithelial barrier and cell function after stress suggests potential clinical importance for patients with impaired or compromised barrier function such as might occur in IBS.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

8 results from studies that gave the peptide. No result from this study comes from people.

01LabEx vivo tissueEfficacy outcome
In ischemia-damaged pig jejunum, linaclotide failed to promote effective epithelial barrier repair, whereas lubiprostone promoted repair.
In plain wordsIn lab tests, linaclotide failed to promote effective repair of damaged pig intestinal barriers, whereas lubiprostone promoted repair.
Peptide
Linaclotide
Outcome
No significant changeEpithelial barrier repair
Study
pign: not reported in source
Ischemia-damaged jejunum
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
active linaclotide failed to effectively promote repair of the epithelial barrier or recovery of short-circuit current, whereas lubiprostone promoted barrier repair and increased short-circuit current.
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393901
02LabEx vivo tissueEfficacy outcome
In ischemia-damaged pig jejunum, linaclotide failed to restore short-circuit current, whereas lubiprostone increased it.
In plain wordsIn lab tests, linaclotide failed to restore electrical current in damaged pig intestine, whereas lubiprostone increased it.
Peptide
Linaclotide
Outcome
No significant changeShort-circuit current recovery
Study
pign: not reported in source
Ischemia-damaged jejunum
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
active linaclotide failed to effectively promote repair of the epithelial barrier or recovery of short-circuit current, whereas lubiprostone promoted barrier repair and increased short-circuit current.
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393902
03LabEx vivo tissueEfficacy outcome
In control pig jejunum, linaclotide and lubiprostone caused similar increases in short-circuit current.
In plain wordsIn lab tests, linaclotide and lubiprostone similarly increased electrical current in control pig intestine.
Peptide
Linaclotide
Outcome
No significant changeShort-circuit current
Study
pign: not reported in source
Control jejunum
Comparator
Lubiprostone 1 μM
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
1 μMAs given in this study (pig).
Source sentences
Summary
In control pig jejunum, 1 μM linaclotide and 1 μM lubiprostone both caused similar increases in short-circuit current (Cl(-) secretion).
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393903
04LabIn vitro (cells)Efficacy outcome
In cytokine-damaged T84 cells, linaclotide was virtually ineffective, whereas lubiprostone protected or promoted barrier and cell function repair.
In plain wordsIn cells, linaclotide was virtually ineffective against cytokine damage, whereas lubiprostone protected or repaired barrier and cell function.
Peptide
Linaclotide
Outcome
No significant changeBarrier and cell function recovery
Study
humann: not reported in source
Cytokine-damaged T84 cells
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
In T84 cells, using measurements of transepithelial resistance, fluxes of fluorescent macromolecules, occludin and mitochondrial membrane potential, active linaclotide was virtually ineffective against damage caused by interferon-γ and tumor necrosis factor-α, while lubiprostone protected or promoted repair of epithelial barrier and cell function.
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393904
05LabIn vitro (cells)Mechanism
In T84 cells, linaclotide increased intracellular cGMP, whereas lubiprostone did not.
In plain wordsIn cells, linaclotide increased cGMP, whereas lubiprostone did not.
Peptide
Linaclotide
Outcome
IncreaseIntracellular cGMP
Study
humann: not reported in source
T84 cells
Outcome group
Receptor activity and mechanism · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
Linaclotide, but not lubiprostone increased [cGMP]i as expected and [Ca(2+)]i and linaclotide depolarized while lubiprostone hyperpolarized the T84 plasma membrane potential suggesting that lubiprostone may lead to greater cellular stability compared to linaclotide.
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393905
06LabIn vitro (cells)Mechanism
In T84 cells, linaclotide increased intracellular calcium, whereas lubiprostone did not.
In plain wordsIn cells, linaclotide increased calcium, whereas lubiprostone did not.
Peptide
Linaclotide
Outcome
IncreaseIntracellular calcium
Study
humann: not reported in source
T84 cells
Outcome group
Receptor activity and mechanism · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
Linaclotide, but not lubiprostone increased [cGMP]i as expected and [Ca(2+)]i and linaclotide depolarized while lubiprostone hyperpolarized the T84 plasma membrane potential suggesting that lubiprostone may lead to greater cellular stability compared to linaclotide.
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393906
07LabIn vitro (cells)Mechanism
In T84 cells, linaclotide depolarized the plasma membrane, whereas lubiprostone hyperpolarized it.
In plain wordsIn cells, linaclotide depolarized the cell membrane, whereas lubiprostone hyperpolarized it.
Peptide
Linaclotide
Outcome
Not applicablePlasma membrane depolarization
Study
humann: not reported in source
T84 cells
Outcome group
Receptor activity and mechanism · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
Linaclotide, but not lubiprostone increased [cGMP]i as expected and [Ca(2+)]i and linaclotide depolarized while lubiprostone hyperpolarized the T84 plasma membrane potential suggesting that lubiprostone may lead to greater cellular stability compared to linaclotide.
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393907
08LabIn vitro (cells)Efficacy outcome
In T84 cells, linaclotide slightly but significantly decreased transepithelial resistance, unlike lubiprostone.
In plain wordsIn cells, linaclotide slightly decreased electrical resistance across the cell layer, unlike lubiprostone.
Peptide
Linaclotide
Outcome
DecreaseTransepithelial resistance
Study
humann: not reported in source
T84 cells
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
In T84 cells, as found with linaclotide but not with lubiprostone, transepithelial resistance was slightly but significantly decreased by guanylin, STa and 8-bromo cGMP and fluorescent dextran fluxes were increased by guanylin.
1 context sentence(design, population, supporting numbers)
Summary · context
Effects of active linaclotide on repair of barrier and cell function in pig jejunum after ischemia and in T84 cells after treatment with proinflammatory cytokines, interferon-γ and tumor necrosis factor-α were examined.
Show in the study text Report a problemFND-2255393908

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
28 Oct 2026, 02:03 UTC
Study results updated
Version 1
27 Oct 2026, 16:34 UTC
First added · source update from Europe PMC

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