Pathological Role and Diagnostic Value of Endogenous Host Defense Peptides in Adult and Neonatal Sepsis

Ho, Jeffery; Zhang, Lin; Liu, Xiao Dong; Wong, Sunny H.; Wang, Maggie Haitian; Lau, Benson Wui-Man; Ngai, Shirley P.C.; Chan, Hung; Choi, Gordon; Leung, C.C.H.; Wong, Wai Tat; Tsang, Sharon; Gin, Tony; Yu, Jun; Chan, Matthew T.V.; Wu, William Ka Kei

doi:10.1097/shk.0000000000000815

Cited by 20 publications

(23 citation statements)

References 89 publications

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“…AMPs work by inserting themselves into the bacterial membrane and forming pores, which result in the leakage of bacterial cytoplasmic content (76)(77)(78). They can also degenerate bacterial cytoplasmic structures and form extracellular net-like structures, which result in bacterial trapping (79).…”

Section: Paneth Cell Role In the Small Intestinementioning

confidence: 99%

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

2020

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Paneth cells were first described in the late 19th century by Gustav Schwalbe and Josef Paneth as columnar epithelial cells possessing prominent eosinophilic granules in their cytoplasm. Decades later there is continued interest in Paneth cells as they play an integral role in maintaining intestinal homeostasis and modulating the physiology of the small intestine and its associated microbial flora. Paneth cells are highly specialized secretory epithelial cells located in the small intestinal crypts of Lieberkühn. The dense granules produced by Paneth cells contain an abundance of antimicrobial peptides and immunomodulating proteins that function to regulate the composition of the intestinal flora. This in turn plays a significant role in secondary regulation of the host microvasculature, the normal injury and repair mechanisms of the intestinal epithelial layer, and the levels of intestinal inflammation. These critical functions may have even more importance in the immature intestine of premature infants. While Paneth cells begin to develop in the middle of human gestation, they do not become immune competent or reach their adult density until closer to term gestation. This leaves preterm infants deficient in normal Paneth cell biology during the greatest window of susceptibility to develop intestinal pathology such as necrotizing enterocolitis (NEC). As 10% of infants worldwide are currently born prematurely, there is a significant population of infants contending with an inadequate cohort of Paneth cells. Infants who have developed NEC have decreased Paneth cell numbers compared to age-matched controls, and ablation of murine Paneth cells results in a NEC-like phenotype suggesting again that Paneth cell function is critical to homeostasis to the immature intestine. This review will provide an up to date and comprehensive look at Paneth cell ontogeny, the impact Paneth cells have on the host-microbial axis in the immature intestine, and the repercussions of Paneth cell dysfunction or loss on injury and repair mechanisms in the immature gut.

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Section: Paneth Cell Role In the Small Intestinementioning

confidence: 99%

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

2020

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“…Cathelicidin is one of the immunomodulatory proteins involved in the pathogenesis of sepsis [29]. Clinical studies have shown that human cathelicidin was 50% lower in critically ill patients with severe sepsis compared to non-septic patients and was further downregulated in septic shock [30].…”

Section: Discussionmentioning

confidence: 99%

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Chan

Liang

et al. 2020

Crit Care

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Objectives: The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated.Design: To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp +/+ ) and knockout (Cnlp −/− ) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. Results: The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms.Conclusions: Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

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“…Among septic patients, the plasma level of hBD‐1 was increased up more than hundred‐fold compared to healthy controls . However, investigators suggested that these innate immunity peptides were warranted further evaluation as septic biomarkers …”

Section: Discussionmentioning

confidence: 99%

“…Human beta-defensin-1 is an endogenous host defence peptide, which is a part of the family of antimicrobial peptides such as heparin-binding protein, lactoferrin, bactericidal/permeability increasing protein (BPI), hepcidin. [19][20][21] The above peptides have been studied in sepsis, (which is defined as a systemic host response to an infection leading to organ failure), as either diagnostic or prognostic biomarkers. Human hBD-1 expression is primarily constitutive while hBD-2 and hBD-3 are inducible during wounding or infection.…”

Section: Discussionmentioning

confidence: 99%

“…21,24 However, investigators suggested that these innate immunity peptides were warranted further evaluation as septic biomarkers. 19 To our knowledge, there is only one study evaluating the importance of variations of hBD-1 levels in humans with liver diseases. According to Kaltsa et al, 25 the values of hBD-1 were elevated in cirrhotic patients, regardless of the aetiology of cirrhosis, compared to those with chronic viral hepatitis or the general population.…”

Section: Discussionmentioning

confidence: 99%

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Human beta‐defensin‐1 is a highly predictive marker of mortality in patients with acute‐on‐chronic liver failure

Mani

Alexopoulou

Vasilieva

et al. 2018

Liver International

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Background & Aim Human beta‐defensin‐1 (hBD‐1) is a natural antimicrobial peptide expressed in the epithelia of multiple tissues including the digestive tract. In the current study, hBD‐1 levels were determined in different subsets of patients with decompensated cirrhosis including acute‐on‐chronic liver failure (ACLF). In addition, the association with mortality of hBD‐1, C‐reactive protein (CRP) and procalcitonin (PCT) was assessed. Methods A total of 125 patients were divided into three groups: 39 with ACLF (derivation cohort), 46 with acute decompensation without ACLF (AD) and 40 with decompensated cirrhosis without an acute event (DC). The data from 24 different ACLF patients were used for validation and 15 healthy individuals as control group. Results Serum hBD‐1, CRP and PCT levels were higher in ACLF compared to both AD and DC groups (P < 0.001). Healthy controls demonstrated similar hBD‐1 and PCT values compared to DC group. In ROC curve, the performance of hBD‐1 to predict 60‐day mortality in ACLF group was similar in derivation and validation cohorts (c‐statistic 0.834 and 0.879, respectively). CRP was a poor predictor of mortality. In ACLF group, patients with high hBD‐1 (>36.625 ng/mL) had a poor prognosis at 60 days compared to those with lower values (log‐rank P = 0.001). In Cox multivariate regression analysis, only hBD‐1 (HR 1.020, 95%CI 1.006‐1.035, P = 0.006) emerged as an independent predictor of death in ACLF group. In AD group, neither hBD‐1 nor PCT or CRP variables were associated with mortality. Conclusions High hBD‐1 was detected at presentation in patients with ACLF who died during follow‐up period. hBD‐1 is an accurate predictor of short‐term mortality in patients with ACLF.

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Pathological Role and Diagnostic Value of Endogenous Host Defense Peptides in Adult and Neonatal Sepsis

Abstract: Innate defense peptides have been insufficiently evaluated as either diagnostic or prognostic biomarkers. In the future, evaluation of host defense peptides as septic biomarkers may employ a longitudinal design and consider a panel of multiple peptides.

Cited by 20 publications

References 89 publications

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Human beta‐defensin‐1 is a highly predictive marker of mortality in patients with acute‐on‐chronic liver failure

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