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Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy.

Sarker P, Ahmed S, Tiash S, Rekha RS, Stromberg R, Andersson J, Bergman P, Gudmundsson GH, Agerberth B, Raqib R - PLoS ONE (2011)

Bottom Line: Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection.Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum.The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon.

View Article: PubMed Central - PubMed

Affiliation: International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh.

ABSTRACT

Background: Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs) that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB) reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia.

Aims: To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB), a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated.

Methods: The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR) and release of the CAP-18 peptide/protein in stool (Western blot).

Principal findings: Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon.

Conclusion: Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from secondary respiratory infections that frequently are the lethal causes in dysentery.

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Related in: MedlinePlus

Comparison between intravenous and oral NaB treatment of Shigella infected rabbits on epithelial CAP-18 immunoreactivity.Immunostaining of CAP-18 peptide/protein was done in the tissue sections of rectum, distal colon and lung from healthy rabbits (n = 5), Shigella-infected rabbits (n = 5), infected rabbits treated with NaB intravenously (IV) (n = 2) or orally (n = 5). A computerized image-analysis technique was applied to quantify the immunoreactive area relative to the total cell area of the epithelia and the results are expressed as ACIA score, i.e., the total positively stained area×total mean intensity (1–256 levels/per pixel) of positive area divided by total cell area (See materials and methods). Data are given as mean ± standard deviation. NaB: Sodium butyrate.
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pone-0020637-g006: Comparison between intravenous and oral NaB treatment of Shigella infected rabbits on epithelial CAP-18 immunoreactivity.Immunostaining of CAP-18 peptide/protein was done in the tissue sections of rectum, distal colon and lung from healthy rabbits (n = 5), Shigella-infected rabbits (n = 5), infected rabbits treated with NaB intravenously (IV) (n = 2) or orally (n = 5). A computerized image-analysis technique was applied to quantify the immunoreactive area relative to the total cell area of the epithelia and the results are expressed as ACIA score, i.e., the total positively stained area×total mean intensity (1–256 levels/per pixel) of positive area divided by total cell area (See materials and methods). Data are given as mean ± standard deviation. NaB: Sodium butyrate.

Mentions: Butyrate is known to disseminate into blood after oral treatment with NaB [16]. We also detected butyrate in rabbit serum in particular at 30 minutes after oral treatment with a single 0.14 mmol dose of NaB (Fig. 5). Moreover, intravenous injection of NaB into Shigella infected rabbits induced CAP-18 peptide/protein expression in the epithelia of lung, rectum and colon (Fig. 6).


Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy.

Sarker P, Ahmed S, Tiash S, Rekha RS, Stromberg R, Andersson J, Bergman P, Gudmundsson GH, Agerberth B, Raqib R - PLoS ONE (2011)

Comparison between intravenous and oral NaB treatment of Shigella infected rabbits on epithelial CAP-18 immunoreactivity.Immunostaining of CAP-18 peptide/protein was done in the tissue sections of rectum, distal colon and lung from healthy rabbits (n = 5), Shigella-infected rabbits (n = 5), infected rabbits treated with NaB intravenously (IV) (n = 2) or orally (n = 5). A computerized image-analysis technique was applied to quantify the immunoreactive area relative to the total cell area of the epithelia and the results are expressed as ACIA score, i.e., the total positively stained area×total mean intensity (1–256 levels/per pixel) of positive area divided by total cell area (See materials and methods). Data are given as mean ± standard deviation. NaB: Sodium butyrate.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108617&req=5

pone-0020637-g006: Comparison between intravenous and oral NaB treatment of Shigella infected rabbits on epithelial CAP-18 immunoreactivity.Immunostaining of CAP-18 peptide/protein was done in the tissue sections of rectum, distal colon and lung from healthy rabbits (n = 5), Shigella-infected rabbits (n = 5), infected rabbits treated with NaB intravenously (IV) (n = 2) or orally (n = 5). A computerized image-analysis technique was applied to quantify the immunoreactive area relative to the total cell area of the epithelia and the results are expressed as ACIA score, i.e., the total positively stained area×total mean intensity (1–256 levels/per pixel) of positive area divided by total cell area (See materials and methods). Data are given as mean ± standard deviation. NaB: Sodium butyrate.
Mentions: Butyrate is known to disseminate into blood after oral treatment with NaB [16]. We also detected butyrate in rabbit serum in particular at 30 minutes after oral treatment with a single 0.14 mmol dose of NaB (Fig. 5). Moreover, intravenous injection of NaB into Shigella infected rabbits induced CAP-18 peptide/protein expression in the epithelia of lung, rectum and colon (Fig. 6).

Bottom Line: Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection.Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum.The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon.

View Article: PubMed Central - PubMed

Affiliation: International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh.

ABSTRACT

Background: Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs) that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB) reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia.

Aims: To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB), a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated.

Methods: The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR) and release of the CAP-18 peptide/protein in stool (Western blot).

Principal findings: Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon.

Conclusion: Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from secondary respiratory infections that frequently are the lethal causes in dysentery.

Show MeSH
Related in: MedlinePlus