Paneth Cell Hyperplasia and Metaplasia in Necrotizing Enterocolitis

Puiman, Patrycja; Paassen, Nanda Burger‐van; Schaart, Maaike W.; Bruijn, Adrianus C. J. M. de; Krijger, Ronald R. de; Tibboel, Dick; Goudoever, Johannes B. van; Renes, Ingrid B.

doi:10.1203/pdr.0b013e3182092a9a

Cited by 39 publications

(53 citation statements)

References 39 publications

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“…However, to the best of our knowledge, an expansion of the Paneth cell population has not been previously documented for ST or other enteric bacterial infections. Only very recently, Paneth cell hyperplasia has been associated with necrotizing enterocolitis in premature infants (48). We found that an activation of the Wnt signaling pathway accompanied the expansion of the Paneth cell population in ST-infected mice.…”

Section: Discussionmentioning

confidence: 64%

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

et al. 2012

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Paneth cells residing at the base of the small intestinal crypts contribute to the mucosal intestinal first line defense by secreting granules filled with antimicrobial polypeptides including lysozyme. These cells derive from the columnar intestinal stem cell located at position 0 and the transit amplifying cell located at position ؉4 in the crypts. We have previously shown that Salmonella enterica serovar Typhimurium (ST), a leading cause of gastrointestinal infections in humans, effects an overall reduction of lysozyme in the small intestine. To extend this work, we examined small-intestinal tissue sections at various time points after ST infection to quantify and localize expression of lysozyme and assess Paneth cell abundance, apoptosis, and the expression of Paneth cell differentiation markers. In response to infection with ST, the intestinal Paneth cell-specific lysozyme content, the number of lysozyme-positive Paneth cells, and the number of granules per Paneth cell decreased. However, this was accompanied by increases in the total number of Paneth cells and the frequency of mitotic events in crypts, by increased staining for the proliferation marker PCNA, primarily at the crypt side walls where the transit amplifying cell resides and not at the crypt base, and by apoptotic events in villi. Furthermore, we found a time-dependent upregulation of first ␤-catenin, followed by EphB3, and lastly Sox9 in response to ST, which was not observed after infection with a Salmonella pathogenicity island 1 mutant deficient in type III secretion. Our data strongly suggest that, in response to ST infection, a Paneth cell differentiation program is initiated that leads to an expansion of the Paneth cell population and that the transit amplifying cell is likely the main progenitor responder. Infection-induced expansion of the Paneth cell population may represent an acute intestinal inflammatory response similar to neutrophilia in systemic infection. Innate mucosal immunity represents the first line of defense against infection by preventing microbes from crossing the gut lining and invading the bloodstream. Paneth cells, located at the base of small intestinal crypts, contribute to the mucosal defense mechanism in the small intestine through the secretion of granules filled with antimicrobial (poly)peptides such as lysozyme, phospholipase A2, defensins (called cryptdins in mice), and RegIII␥ (12,42,44,51). Lysozyme is a bimodal polypeptide of approximately 14 kDa that hydrolyzes peptidoglycan (20) and also directly disrupts membranes, similar to antimicrobial peptides (29). In mice, two lysozyme genes are transcribed (27): one in myeloid cells (M lysozyme) and one in epithelial cells, in particular Paneth cells (P lysozyme). These two lysozymes share 92% homology but differ in their net charge with P lysozyme being more positively charged than M lysozyme (37).In the small intestine, the intestinal stem cell located in the crypts gives rise to Paneth cells, as well as enterocytes, goblet cells, and enteroendocrine cells (55...

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Section: Discussionmentioning

confidence: 64%

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

et al. 2012

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“…The present study suggests that HD5 expression coincides with PC development until a GA of 28 wk; in the period starting from 29 wk of GA, HD5 expression increases more rapidly than the number of PCs. PCs with their defensin expression, such as HD5, play a key role in the intestinal innate immunity and development of diseases (13)(14)(15). PCs with their defensin expression are previously described in the pathophysiology of Crohn's disease (15).…”

Section: Discussionmentioning

confidence: 99%

Paneth cells in the developing gut: when do they arise and when are they immune competent?

et al. 2016

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Background:Little is known about the perinatal development of Paneth cells (PCs) during gestation and the relation with necrotizing enterocolitis (NEC). We aimed to investigate when PCs arise and when they become immune competent during gestation. Methods: We included 57 samples of ileum tissue of fetuses/ infants with a gestional age (GA) between 9 and 40 wk taken as part of a standard autopsy procedure. Hematoxylin-eosin staining and anti-human defensin 5 immunohistochemistry were performed. We performed a semi-quantitative assessment of (immune-competent) PC numbers per 10 crypts per tissue section per GA. results: The number of PCs and the number of immunecompetent PCs increased with increasing GA (Spearman's ρ = 0.41, P = 0.002 and ρ = 0.61, P < 0.001, respectively). Whereas significantly higher PC numbers were observed after 37 wk gestation (median 7, range 0-12) compared to preterm infants (median 0, range 0-15; P = 0.002), we counted higher numbers of immune-competent PCs already in infants with GA above 29 wk (median 6, range 0-18) compared to infants with GA under 29 wk (median 2, range 0-9; P < 0.001). conclusion: The significant increase of immune-competent PCs starting from a GA of 29 wk mimics the rise in incidence of NEC during a similar postmenstrual age in preterm infants.P aneth cells (PCs) are specialized epithelial immune cells located in the base of the crypts of Lieberkühn located in the small intestine (1,2). PCs can be seen in the gut by the first trimester and are thought to mature during gestation (1,2). PCs protect the intestinal stem cells from pathogens by stimulating stem cell differentiation, shaping the intestinal microbiota, and assist in reparation of the gut (2). To this end, they secrete (among other things) human α-defensins (HD5/HD6) (3). These defensins protect the intestinal mucosa against bacterial invasion, and are thought to be associated with initiating and adapting immunity (3). How PCs develop after the first trimester and when PCs become immune competent remains uncertain.PCs are thought to play a role in the development of NEC, a common and devastating disease most commonly observed in preterm infants (4-6). NEC involves the preterm intestine and has a complex pathophysiology in which bacterial invasion and an excessive inflammatory response is an important contributing factor (5,6). Unfortunately, the exact pathophysiology is incompletely understood.It has been hypothesized that maturation of immune-competent PCs is crucial for NEC development (4,(6)(7)(8). In the preterm gut, PCs secrete defensins that might contribute to an excessive inflammatory response as observed in NEC (4). This hypothesis is derived from the observation that extremely-low-birth-weight human infants generally have the longest interval before the onset of NEC-with a peak incidence at the postmenstrual age of 29-33 wk (4,6-8). Despite the possible role for PC-maturation in the pathophysiology of NEC, little is known about PC-maturation and functioning in the immature intestine. Therefore, we ...

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“…34,35 The barrier function of the preterm gastrointestinal tract is immature, both in its structure and secretory activity. [36][37][38][39][40] Mucosal permeability of the preterm gut is higher compared …”

Section: Risk Factors Associated With Nec Prematurity and Low Birth Wmentioning

confidence: 99%

“…37 In preterm infants affected by NEC, mucosal injury has been shown to lead to increased nitric oxide production which, in turn, accentuates epithelial injury, thus increasing the susceptibility to NEC. 38 The preterm gut affected by NEC has also been shown to have fewer and immature Paneth cells 15,39 (specialized crypt cells in the human intestine producing natural antimicrobials, such as lysozyme) with near absence of lysozyme. 40 The immature nature of the preterm immune system is thought to play a major role in the development of NEC.…”

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confidence: 99%

Necrotizing enterocolitis: current perspectives

Yajamanyam

Rasiah²,

Ewer³

2014

RRN

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Necrotizing enterocolitis is the most common gastrointestinal emergency in neonates, particularly in those born very preterm. It is a leading cause of morbidity and mortality, especially in extremely low birth weight infants. Despite extensive research, the pathophysiology of necrotizing enterocolitis remains unclear and therapeutic options are limited. Multiple risk factors have been reported, but most are associated with prematurity and its complications. This makes management very challenging in vulnerable preterm infants. In this review, we focus on the risk factors and some of the current research in this area, particularly studies aimed at early detection and potential preventive measures for this potentially lethal condition.

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Paneth Cell Hyperplasia and Metaplasia in Necrotizing Enterocolitis

Cited by 39 publications

References 39 publications

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

Paneth cells in the developing gut: when do they arise and when are they immune competent?

Necrotizing enterocolitis: current perspectives

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