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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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CAP-18 expression in various mucosal tissues of healthy, infected, infected and PB/NaB treated rabbits.Immunohistochemical technique was utilized to detect CAP-18 peptide/protein expression (brown staining) in the mucosal tissue sections of rectum, distal colon, lung and trachea from healthy rabbits, Shigella-infected rabbits and infected rabbits treated orally with PB or NaB. Representative pictures are shown. Original magnification was ×400 for all except for lung which was ×600. Row 1. The expression of CAP-18 in enterocytes in the surface epithelium of rectum was reduced in infected rabbit compared to healthy rabbit. CAP-18 expression in the surface epithelium of rectum in infected rabbit increased after treatment with PB or NaB. Row 2. CAP-18 expression in the distal colon was decreased in enterocytes in the surface epithelium in infected rabbit compared to healthy rabbit. NaB amplified the CAP-18 expression in the surface epithelium of colon in infected rabbit, while PB exhibited no apparent effect. Row 3. In lung, CAP-18 expression was located in the ciliated and mucus cells in the epithelial layer and in the alveolar macrophages. Decreased expression of CAP-18 was observed in the lung epithelial layer of infected rabbit compared to healthy rabbit. PB or NaB treatment led to increased expression of CAP-18 peptide in the lung epithelial lining of infected rabbit. Row 4. CAP-18 expression was localized to the ciliated epithelium of the trachea. CAP-18 peptide was downregulated in the tracheal epithelium of infected rabbit in comparison with healthy rabbit. Treatment with NaB counteracted this downregulation, while treatment with PB had no obvious effect. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate.
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pone-0020637-g003: CAP-18 expression in various mucosal tissues of healthy, infected, infected and PB/NaB treated rabbits.Immunohistochemical technique was utilized to detect CAP-18 peptide/protein expression (brown staining) in the mucosal tissue sections of rectum, distal colon, lung and trachea from healthy rabbits, Shigella-infected rabbits and infected rabbits treated orally with PB or NaB. Representative pictures are shown. Original magnification was ×400 for all except for lung which was ×600. Row 1. The expression of CAP-18 in enterocytes in the surface epithelium of rectum was reduced in infected rabbit compared to healthy rabbit. CAP-18 expression in the surface epithelium of rectum in infected rabbit increased after treatment with PB or NaB. Row 2. CAP-18 expression in the distal colon was decreased in enterocytes in the surface epithelium in infected rabbit compared to healthy rabbit. NaB amplified the CAP-18 expression in the surface epithelium of colon in infected rabbit, while PB exhibited no apparent effect. Row 3. In lung, CAP-18 expression was located in the ciliated and mucus cells in the epithelial layer and in the alveolar macrophages. Decreased expression of CAP-18 was observed in the lung epithelial layer of infected rabbit compared to healthy rabbit. PB or NaB treatment led to increased expression of CAP-18 peptide in the lung epithelial lining of infected rabbit. Row 4. CAP-18 expression was localized to the ciliated epithelium of the trachea. CAP-18 peptide was downregulated in the tracheal epithelium of infected rabbit in comparison with healthy rabbit. Treatment with NaB counteracted this downregulation, while treatment with PB had no obvious effect. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate.

Mentions: Immunohistochemical analyses (Fig. 3 and 4) revealed significant downregulation of CAP-18 peptide/protein after Shigella infection in the epithelia of rectum (p = 0.008) and distal colon (p≤0.001) compared to healthy rabbits. This is in line with our previous result [11]. Interestingly, we also detected a significant downregulation of epithelial CAP-18 in the lung (p = 0.001) and trachea (p = 0.016) after Shigella infection compared to healthy rabbits. No obvious changes in CAP-18 peptide/protein expression were observed in the non-epithelial region of the organs investigated (Fig. 3).


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 expression in various mucosal tissues of healthy, infected, infected and PB/NaB treated rabbits.Immunohistochemical technique was utilized to detect CAP-18 peptide/protein expression (brown staining) in the mucosal tissue sections of rectum, distal colon, lung and trachea from healthy rabbits, Shigella-infected rabbits and infected rabbits treated orally with PB or NaB. Representative pictures are shown. Original magnification was ×400 for all except for lung which was ×600. Row 1. The expression of CAP-18 in enterocytes in the surface epithelium of rectum was reduced in infected rabbit compared to healthy rabbit. CAP-18 expression in the surface epithelium of rectum in infected rabbit increased after treatment with PB or NaB. Row 2. CAP-18 expression in the distal colon was decreased in enterocytes in the surface epithelium in infected rabbit compared to healthy rabbit. NaB amplified the CAP-18 expression in the surface epithelium of colon in infected rabbit, while PB exhibited no apparent effect. Row 3. In lung, CAP-18 expression was located in the ciliated and mucus cells in the epithelial layer and in the alveolar macrophages. Decreased expression of CAP-18 was observed in the lung epithelial layer of infected rabbit compared to healthy rabbit. PB or NaB treatment led to increased expression of CAP-18 peptide in the lung epithelial lining of infected rabbit. Row 4. CAP-18 expression was localized to the ciliated epithelium of the trachea. CAP-18 peptide was downregulated in the tracheal epithelium of infected rabbit in comparison with healthy rabbit. Treatment with NaB counteracted this downregulation, while treatment with PB had no obvious effect. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate.
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pone-0020637-g003: CAP-18 expression in various mucosal tissues of healthy, infected, infected and PB/NaB treated rabbits.Immunohistochemical technique was utilized to detect CAP-18 peptide/protein expression (brown staining) in the mucosal tissue sections of rectum, distal colon, lung and trachea from healthy rabbits, Shigella-infected rabbits and infected rabbits treated orally with PB or NaB. Representative pictures are shown. Original magnification was ×400 for all except for lung which was ×600. Row 1. The expression of CAP-18 in enterocytes in the surface epithelium of rectum was reduced in infected rabbit compared to healthy rabbit. CAP-18 expression in the surface epithelium of rectum in infected rabbit increased after treatment with PB or NaB. Row 2. CAP-18 expression in the distal colon was decreased in enterocytes in the surface epithelium in infected rabbit compared to healthy rabbit. NaB amplified the CAP-18 expression in the surface epithelium of colon in infected rabbit, while PB exhibited no apparent effect. Row 3. In lung, CAP-18 expression was located in the ciliated and mucus cells in the epithelial layer and in the alveolar macrophages. Decreased expression of CAP-18 was observed in the lung epithelial layer of infected rabbit compared to healthy rabbit. PB or NaB treatment led to increased expression of CAP-18 peptide in the lung epithelial lining of infected rabbit. Row 4. CAP-18 expression was localized to the ciliated epithelium of the trachea. CAP-18 peptide was downregulated in the tracheal epithelium of infected rabbit in comparison with healthy rabbit. Treatment with NaB counteracted this downregulation, while treatment with PB had no obvious effect. PB: Sodium 4-phenylbutyrate, NaB: Sodium butyrate.
Mentions: Immunohistochemical analyses (Fig. 3 and 4) revealed significant downregulation of CAP-18 peptide/protein after Shigella infection in the epithelia of rectum (p = 0.008) and distal colon (p≤0.001) compared to healthy rabbits. This is in line with our previous result [11]. Interestingly, we also detected a significant downregulation of epithelial CAP-18 in the lung (p = 0.001) and trachea (p = 0.016) after Shigella infection compared to healthy rabbits. No obvious changes in CAP-18 peptide/protein expression were observed in the non-epithelial region of the organs investigated (Fig. 3).

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