Cord Blood Antimicrobial Peptide LL37 Levels in Preterm Neonates and Association with Preterm Complications

Overview

Journal Ital J Pediatr

Publisher Biomed Central

Specialty Pediatrics

Date 2022 Jul 8

PMID 35804392

Authors

Zhuxiao Ren

Wenhui Mo

Liling Yang

Jianlan Wang

Qi Zhang

Zhicheng Zhong

Wei Wei

Zhipeng Liu

Zhiping Wu

Yao Yao

Jie Yang

Affiliations

Soon will be listed here.

Abstract

Background: Cathelicidin/LL-37 plays a significant role in the human immune defense reaction. Preterm human immature organs being exposed to inflammation-induced injury was the critical denominator leading to the common preterm associated complications. Previous study showed LL37 concentration in preterm neonates was lower in tracheal aspirates and breast milk as compared to term infants. An adults study showed decreased LL-37 levels was a risk factor for patients in developing severe chronic obstructive pulmonary disease (COPD). However, little is known about the regulation of human cord blood LL37 in preterm neonates and the association with preterm complications. This study was designed to investigate the concentration of LL37 in cord blood of preterm infants and correlation with preterm complications.

Methods: Singleton infants born in June 2017 to August 2021 in the study hospital were enrolled. Maternal and neonatal clinical characteristics were collected. LL37 levels, pro-inflammatory factor interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) in cord blood and LL37 levels in serum 48-72 hours after birth were measured by enzyme-linked immunosorbent assay. The serum level of LL37 in preterm and term neonates were compared, the perinatal factors possibly affecting the LL37 levels were investigated and the relationship between LL37 level and preterm outcomes were analyzed.

Results: Cord blood LL37 levels in preterm infants were lower than that in term neonates. Cord blood LL37 level was positively correlated with gestational age in preterm. Prenatal steroid administration in preterm neonates decreased cord blood LL37 level. LL37 level was obviously lower in patients with bronchopulmonary dysplasia (BPD). Multiple line regression analysis showed higher LL37 level in cord blood was an independent protective factor for BPD. The concentration of pro-inflammatory factor IL-6 was negatively correlated with LL37.

Conclusion: Cord blood LL37 levels increased during gestation and decreased after perinatal steroid usage. Very preterm infants who displayed higher cord blood LL37 level had reduced risk of developing BPD. Regulation of pro-inflammatory cytokine IL-6 may be associated with the protective effect of LL37 on BPD.

Citing Articles

Antimicrobial Peptides (AMPs) and the Microbiome in Preterm Infants: Consequences and Opportunities for Future Therapeutics.

Marissen J, Reichert L, Hartel C, Fortmann M, Faust K, Msanga D Int J Mol Sci. 2024; 25(12).

PMID: 38928389 PMC: 11203687. DOI: 10.3390/ijms25126684.

Nasal cathelicidin is expressed in early life and is increased during mild, but not severe respiratory syncytial virus infection.

Sintoris S, Binkowska J, Gillan J, Zuurbier R, Twynam-Perkins J, Kristensen M Sci Rep. 2024; 14(1):13928.

PMID: 38886476 PMC: 11182768. DOI: 10.1038/s41598-024-64446-1.

Antimicrobial peptide LL37 and regulatory T cell associated with late-onset sepsis in very preterm infants.

Zhuxiao R, Shuo Y, Jiangxue H, Jingjun P, Qi Z, Zhu W iScience. 2024; 27(5):109780.

PMID: 38736551 PMC: 11088333. DOI: 10.1016/j.isci.2024.109780.

Cord blood stem cell‑derived Angptl7 ameliorates the severity of bronchopulmonary dysplasia via anti‑inflammatory and proangiogenic effects.

Ren Z, Yang L, Wang J, Han J, Lin S, Yao Y Mol Med Rep. 2023; 29(1).

PMID: 37997800 PMC: 10704546. DOI: 10.3892/mmr.2023.13131.

References

Speer C . Inflammation and bronchopulmonary dysplasia: a continuing story. Semin Fetal Neonatal Med. 2006; 11(5):354-62. DOI: 10.1016/j.siny.2006.03.004. View

Ramos-Martinez E, Lopez-Vancell M, Fernandez de Cordova-Aguirre J, Rojas-Serrano J, Chavarria A, Velasco-Medina A . Reduction of respiratory infections in asthma patients supplemented with vitamin D is related to increased serum IL-10 and IFNγ levels and cathelicidin expression. Cytokine. 2018; 108:239-246. DOI: 10.1016/j.cyto.2018.01.001. View

Scheid A, Li N, Jeffers C, Borriello F, Joshi S, Ozonoff A . Antimicrobial peptide LL-37 and recombinant human mannose-binding lectin express distinct age- and pathogen-specific antimicrobial activity in human newborn cord blood . F1000Res. 2018; 7:616. PMC: 6143923. DOI: 10.12688/f1000research.14736.1. View

Murakami M, Dorschner R, Stern L, Lin K, Gallo R . Expression and secretion of cathelicidin antimicrobial peptides in murine mammary glands and human milk. Pediatr Res. 2004; 57(1):10-5. DOI: 10.1203/01.PDR.0000148068.32201.50. View

Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee J . Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010; 28(12):2229-38. PMC: 3293245. DOI: 10.1002/stem.544. View

Rudloff I, Cho S, Bui C, McLean C, Veldman A, Berger P . Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia. J Cell Mol Med. 2016; 21(6):1128-1138. PMC: 5431131. DOI: 10.1111/jcmm.13044. View

Mandic Havelka A, Yektaei-Karin E, Hultenby K, Sorensen O, Lundahl J, Berggren V . Maternal plasma level of antimicrobial peptide LL37 is a major determinant factor of neonatal plasma LL37 level. Acta Paediatr. 2010; 99(6):836-41. DOI: 10.1111/j.1651-2227.2010.01726.x. View

Bhandari V . Postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol. 2014; 100(3):189-201. PMC: 4023567. DOI: 10.1002/bdra.23220. View

Patel R, Ferguson J, McElroy S, Khashu M, Caplan M . Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res. 2020; 88(Suppl 1):10-15. PMC: 8096612. DOI: 10.1038/s41390-020-1074-4. View

10.

Surate Solaligue D, Rodriguez-Castillo J, Ahlbrecht K, Morty R . Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2017; 313(6):L1101-L1153. DOI: 10.1152/ajplung.00343.2017. View

11.

Hizal M, Bruni C, Romano E, Mazzotta C, Guiducci S, Bellando Randone S . Decrease of LL-37 in systemic sclerosis: a new marker for interstitial lung disease?. Clin Rheumatol. 2015; 34(4):795-8. DOI: 10.1007/s10067-014-2854-1. View

12.

Majewski K, Agier J, Kozlowska E, Brzezinska-Blaszczyk E . Serum level of cathelicidin LL-37 in patients with active tuberculosis and other infectious diseases. J Biol Regul Homeost Agents. 2017; 31(3):731-736. View

13.

Savani R . Modulators of inflammation in Bronchopulmonary Dysplasia. Semin Perinatol. 2018; 42(7):459-470. PMC: 6368974. DOI: 10.1053/j.semperi.2018.09.009. View

14.

Yoshio H, Lagercrantz H, Gudmundsson G, Agerberth B . First line of defense in early human life. Semin Perinatol. 2004; 28(4):304-11. DOI: 10.1053/j.semperi.2004.08.008. View

15.

Hitchon C, Meng X, El Gabalawy H, Larcombe L . Human host defence peptide LL37 and anti-cyclic citrullinated peptide antibody in early inflammatory arthritis. RMD Open. 2019; 5(1):e000874. PMC: 6560668. DOI: 10.1136/rmdopen-2018-000874. View

16.

Starner T, Agerberth B, Gudmundsson G, McCray Jr P . Expression and activity of beta-defensins and LL-37 in the developing human lung. J Immunol. 2005; 174(3):1608-15. DOI: 10.4049/jimmunol.174.3.1608. View

17.

Uysal P, Simsek G, Durmus S, Sozer V, Aksan H, Yurt S . Evaluation of plasma antimicrobial peptide LL-37 and nuclear factor-kappaB levels in stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2019; 14:321-330. PMC: 6354692. DOI: 10.2147/COPD.S185602. View

18.

Murakami M, Lopez-Garcia B, Braff M, Dorschner R, Gallo R . Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. J Immunol. 2004; 172(5):3070-7. DOI: 10.4049/jimmunol.172.5.3070. View

19.

Schaller-Bals S, Schulze A, Bals R . Increased levels of antimicrobial peptides in tracheal aspirates of newborn infants during infection. Am J Respir Crit Care Med. 2002; 165(7):992-5. DOI: 10.1164/ajrccm.165.7.200110-020. View

20.

Aidoukovitch A, Anders E, Dahl S, Nebel D, Svensson D, Nilsson B . The host defense peptide LL-37 is internalized by human periodontal ligament cells and prevents LPS-induced MCP-1 production. J Periodontal Res. 2019; 54(6):662-670. DOI: 10.1111/jre.12667. View