Limits...
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.

Show MeSH

Related in: MedlinePlus

CAP-18 in stool of healthy rabbits, Shigella infected rabbits and infected rabbit treated with PB.Western blot analysis of CAP-18 peptide/protein in stool extracts from 2 healthy, 2 Shigella infected and 1 infected rabbit treated with PB are shown. The 17 kDa pro-form of CAP-18 was detected in the stool of healthy and infected rabbits before treatment. PB treatment resulted in increased levels of the pro-form and appearance of low levels of the active CAP-18 peptide at day 2 (D2) and day 3 (D3); the level of active peptide was higher at day 4 (D4) that faded at day 5 (D5). Synthetic CAP-18 peptide (1 ng) served as positive control. PB: Sodium 4-phenylbutyrate.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3108617&req=5

pone-0020637-g002: CAP-18 in stool of healthy rabbits, Shigella infected rabbits and infected rabbit treated with PB.Western blot analysis of CAP-18 peptide/protein in stool extracts from 2 healthy, 2 Shigella infected and 1 infected rabbit treated with PB are shown. The 17 kDa pro-form of CAP-18 was detected in the stool of healthy and infected rabbits before treatment. PB treatment resulted in increased levels of the pro-form and appearance of low levels of the active CAP-18 peptide at day 2 (D2) and day 3 (D3); the level of active peptide was higher at day 4 (D4) that faded at day 5 (D5). Synthetic CAP-18 peptide (1 ng) served as positive control. PB: Sodium 4-phenylbutyrate.

Mentions: By Western blot analysis of CAP-18 in stool extracts, only pro-form of CAP-18 was observed in healthy and infected rabbits, although band intensity varied between individual rabbits (Fig. 2). As mentioned in the previous section, with PB treatment, stool from only one rabbit could be obtained throughout the treatment regime. In stool extracts from that single rabbit, the pro-form was detected at higher levels from day 2 to 5. The processed form of CAP-18 was also detected at low levels from day 2 to 5 (Fig. 2). In the obtained stool samples at day 1, 2 and 5 from other PB treated rabbits, higher levels of CAP-18 pro-form and low levels of active peptide were also observed after treatment (not shown). The effect of NaB has been demonstrated in our previous study [11] and was reproduced here (not shown).


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)

CAP-18 in stool of healthy rabbits, Shigella infected rabbits and infected rabbit treated with PB.Western blot analysis of CAP-18 peptide/protein in stool extracts from 2 healthy, 2 Shigella infected and 1 infected rabbit treated with PB are shown. The 17 kDa pro-form of CAP-18 was detected in the stool of healthy and infected rabbits before treatment. PB treatment resulted in increased levels of the pro-form and appearance of low levels of the active CAP-18 peptide at day 2 (D2) and day 3 (D3); the level of active peptide was higher at day 4 (D4) that faded at day 5 (D5). Synthetic CAP-18 peptide (1 ng) served as positive control. PB: Sodium 4-phenylbutyrate.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020637-g002: CAP-18 in stool of healthy rabbits, Shigella infected rabbits and infected rabbit treated with PB.Western blot analysis of CAP-18 peptide/protein in stool extracts from 2 healthy, 2 Shigella infected and 1 infected rabbit treated with PB are shown. The 17 kDa pro-form of CAP-18 was detected in the stool of healthy and infected rabbits before treatment. PB treatment resulted in increased levels of the pro-form and appearance of low levels of the active CAP-18 peptide at day 2 (D2) and day 3 (D3); the level of active peptide was higher at day 4 (D4) that faded at day 5 (D5). Synthetic CAP-18 peptide (1 ng) served as positive control. PB: Sodium 4-phenylbutyrate.
Mentions: By Western blot analysis of CAP-18 in stool extracts, only pro-form of CAP-18 was observed in healthy and infected rabbits, although band intensity varied between individual rabbits (Fig. 2). As mentioned in the previous section, with PB treatment, stool from only one rabbit could be obtained throughout the treatment regime. In stool extracts from that single rabbit, the pro-form was detected at higher levels from day 2 to 5. The processed form of CAP-18 was also detected at low levels from day 2 to 5 (Fig. 2). In the obtained stool samples at day 1, 2 and 5 from other PB treated rabbits, higher levels of CAP-18 pro-form and low levels of active peptide were also observed after treatment (not shown). The effect of NaB has been demonstrated in our previous study [11] and was reproduced here (not shown).

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