Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice.
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. During NEC pathogenesis, bacteria are able to penetrate innate immune defenses and invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Normally, Paneth cells appear in the intestinal crypts during the first trimester of human pregnancy. Paneth cells constitute a major component of the innate immune system by producing multiple antimicrobial peptides and proinflammatory mediators. To better understand the possible role of Paneth cell disruption in NEC, we quantified the number of Paneth cells present in infants with NEC and found that they were significantly decreased compared with age-matched controls. We were able to model this loss in the intestine of postnatal day (P)14-P16 (immature) mice by treating them with the zinc chelator dithizone. Intestines from dithizone-treated animals retained approximately half the number of Paneth cells compared with controls. Furthermore, by combining dithizone treatment with exposure to Klebsiella pneumoniae, we were able to induce intestinal injury and inflammatory induction that resembles human NEC. Additionally, this novel Paneth cell ablation model produces NEC-like pathology that is consistent with other currently used animal models, but this technique is simpler to use, can be used in older animals that have been dam fed, and represents a novel line of investigation to study NEC pathogenesis and treatment.
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Chunxian
C
Zhang
Michael P
MP
Sherman
Lawrence S
LS
Prince
David
D
Bader
Jörn-Hendrik
JH
Weitkamp
James C
JC
Slaughter
Steven J
SJ
McElroy
D000375:Aging / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000378:metabolism; D004195:Disease Models, Animal; D004230:Dithizone; D004750:Enteral Nutrition; D020345:Enterocolitis, Necrotizing / Q000150:complications / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology*; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000150:complications / Q000382:microbiology / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D019879:Paneth Cells / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology*; D015032:Zinc / Q000494:pharmacology / Q000627:therapeutic use
D004230:Dithizone; D015032:Zinc