title: Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy.
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.
  
  
  OBJECTIVE
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh.
authors.forename: Protim
authors.initials: P
authors.lastname: Sarker
authors.forename: Sultan
authors.initials: S
authors.lastname: Ahmed
authors.forename: Snigdha
authors.initials: S
authors.lastname: Tiash
authors.forename: Rokeya Sultana
authors.initials: RS
authors.lastname: Rekha
authors.forename: Roger
authors.initials: R
authors.lastname: Stromberg
authors.forename: Jan
authors.initials: J
authors.lastname: Andersson
authors.forename: Peter
authors.initials: P
authors.lastname: Bergman
authors.forename: Gudmundur H
authors.initials: GH
authors.lastname: Gudmundsson
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.forename: Rubhana
authors.initials: R
authors.lastname: Raqib
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D058491:Bacterial Load / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D004405:Dysentery, Bacillary / Q000188:drug therapy; D005243:Feces / Q000382:microbiology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D007420:Intestine, Large / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D008969:Molecular Sequence Data; D010654:Phenylbutyrates / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D012760:Shigella / Q000187:drug effects* / Q000472:pathogenicity; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D010654:Phenylbutyrates; D012333:RNA, Messenger; D054804:Cathelicidins