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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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Changes of infection associated events in Shigella infected rabbits before, during and after PB/NaB treatment.(A) Body weight loss due to Shigella infection was recovered by treatment with PB or NaB. Data are given as mean ± standard deviation of 5 rabbits in each group. Two-way ANOVA with repeated measures on one factor (time) was used in comparing the effects over time between different groups. The differences are significant when P<0.05; *significant loss of body weight compared to day 0 (healthy condition), ‡significant recovery compared to day 2. (B) Kaplan-Meier survival plot revealed reduction of Shigella CFU in stool of infected rabbits treated with PB (n = 5) or NaB (n = 5).Infected untreated rabbits were sacrificed at day 2. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate, CFU: Colony forming unit.
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pone-0020637-g001: Changes of infection associated events in Shigella infected rabbits before, during and after PB/NaB treatment.(A) Body weight loss due to Shigella infection was recovered by treatment with PB or NaB. Data are given as mean ± standard deviation of 5 rabbits in each group. Two-way ANOVA with repeated measures on one factor (time) was used in comparing the effects over time between different groups. The differences are significant when P<0.05; *significant loss of body weight compared to day 0 (healthy condition), ‡significant recovery compared to day 2. (B) Kaplan-Meier survival plot revealed reduction of Shigella CFU in stool of infected rabbits treated with PB (n = 5) or NaB (n = 5).Infected untreated rabbits were sacrificed at day 2. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate, CFU: Colony forming unit.

Mentions: Infected rabbits developed dysentery with thick liquid stool and mucus, occasional blood in stool, reduced body weight, transient fever, lethargy and anorexia, usually after 24 hours of infection. Infected rabbits died within 48 hours if kept untreated. In contrast, treated rabbits survived and recovered from the disease within 3–5 days of treatment as apparent by formed stool and revival from lethargy and anorexia. The initial body weight loss, what was prominent up to 2 days after infection was recovered by treatment with PB or NaB (Fig. 1 A). The recovery of body weight by NaB treatment was steady over time, while PB treatment led to a significant recovery at day 3. Reduction of fever, pus cells, macrophages and red blood cells were comparable in the 2 treatment groups (not shown). Thus, PB appears to ameliorate the clinical symptoms of shigellosis in the rabbit model as demonstrated earlier for NaB [11]. Since untreated infected rabbits could not survive for longer period, the clinical features could not be compared between treated and untreated rabbits.


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)

Changes of infection associated events in Shigella infected rabbits before, during and after PB/NaB treatment.(A) Body weight loss due to Shigella infection was recovered by treatment with PB or NaB. Data are given as mean ± standard deviation of 5 rabbits in each group. Two-way ANOVA with repeated measures on one factor (time) was used in comparing the effects over time between different groups. The differences are significant when P<0.05; *significant loss of body weight compared to day 0 (healthy condition), ‡significant recovery compared to day 2. (B) Kaplan-Meier survival plot revealed reduction of Shigella CFU in stool of infected rabbits treated with PB (n = 5) or NaB (n = 5).Infected untreated rabbits were sacrificed at day 2. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate, CFU: Colony forming unit.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020637-g001: Changes of infection associated events in Shigella infected rabbits before, during and after PB/NaB treatment.(A) Body weight loss due to Shigella infection was recovered by treatment with PB or NaB. Data are given as mean ± standard deviation of 5 rabbits in each group. Two-way ANOVA with repeated measures on one factor (time) was used in comparing the effects over time between different groups. The differences are significant when P<0.05; *significant loss of body weight compared to day 0 (healthy condition), ‡significant recovery compared to day 2. (B) Kaplan-Meier survival plot revealed reduction of Shigella CFU in stool of infected rabbits treated with PB (n = 5) or NaB (n = 5).Infected untreated rabbits were sacrificed at day 2. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate, CFU: Colony forming unit.
Mentions: Infected rabbits developed dysentery with thick liquid stool and mucus, occasional blood in stool, reduced body weight, transient fever, lethargy and anorexia, usually after 24 hours of infection. Infected rabbits died within 48 hours if kept untreated. In contrast, treated rabbits survived and recovered from the disease within 3–5 days of treatment as apparent by formed stool and revival from lethargy and anorexia. The initial body weight loss, what was prominent up to 2 days after infection was recovered by treatment with PB or NaB (Fig. 1 A). The recovery of body weight by NaB treatment was steady over time, while PB treatment led to a significant recovery at day 3. Reduction of fever, pus cells, macrophages and red blood cells were comparable in the 2 treatment groups (not shown). Thus, PB appears to ameliorate the clinical symptoms of shigellosis in the rabbit model as demonstrated earlier for NaB [11]. Since untreated infected rabbits could not survive for longer period, the clinical features could not be compared between treated and untreated rabbits.

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