Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma

Liu,Maohua; Zhang,Jingxiu; Liu,Chengjun

doi:10.3892/etm.2017.5376

Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma

Authors:
- Maohua Liu
- Jingxiu Zhang
- Chengjun Liu
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Affiliations: Department of Pediatric Internal Medicine Ward 1, Yishui Central Hospital of Linyi, Linyi, Shandong 276400, P.R. China, Department of Pediatric Internal Medicine Ward 3, Yishui Central Hospital of Linyi, Linyi, Shandong 276400, P.R. China
Published online on: October 25, 2017 https://doi.org/10.3892/etm.2017.5376
Pages: 539-547

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Abstract

Pediatric asthma is a chronic pulmonary inflammatory disease featuring hypersecretion of mucus and inflammation in the airway, resulting in dysfunction of the airway smooth muscle. Previous evidence demonstrated that latrophilins, a novel family of receptors, present a beneficial effect on airway smooth muscle cells. In the present study, the therapeutic effects of recombinant human latrophilin 3 (rhLPHN3) antibody (Ab) in patients with pediatric asthma were investigated, and the molecular mechanism underlying the function of LPHN3 in the treatment of asthma in clinical practice was examined. A total of 342 pediatric asthma cases were recruited and randomly divided into three groups, receiving treatment with rhLPHN3 Ab (n=134), salbutamol (n=108) or montelukast (n=100) by nasal aerosolization. Each group received the respective clinically tested dose for 16 weeks. Inflammatory factors interleukin (IL)‑10, IL‑17, IL‑4, matrix metallopeptidase‑9 (MMP‑9), interferon‑γ (IFN‑γ) and transforming growth factor‑β (TGF‑β) levels in peripheral blood mononuclear cells were analyzed prior to and post treatment. The clinical outcomes revealed that pathological alterations were significantly improved following treatment with rhLPHN3 Ab for patients with pediatric asthma when compared with those receiving salbutamol and montelukast. It was also observed that rhLPHN3 Ab downregulated the plasma concentration levels of IL‑10, IL‑17, IL‑4 and MMP‑9, and upregulated IFN‑γ and TGF‑β levels in the three groups. In addition, clinical data demonstrated that rhLPHN3 Ab significantly promoted E‑selectin and mucin 5AC expression, as well as improved the activation of nuclear factor (NF)‑κB p65 DNA binding activity and the phosphorylation levels of protein kinase A. Furthermore, rhLPHN3 Ab markedly improved adhesion and proliferation of airway smooth muscle cells, which led to promotion of the contraction of these cells.In conclusion, these clinical data suggest that rhLPHN3 Ab serves an important role in the inhibition of inflammatory mediators through downregulation of NF‑κB signaling pathway, which contributes to airway remodeling and bronchodilation in patients with pediatric asthma.

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1	Rubin BK: Asthma 2015: The year in review. Respir Care. 61:556–559. 2016. View Article : Google Scholar : PubMed/NCBI
2	Rodriguez-Villamizar LA, Berney C, Villa-Roel C, Ospina MB, Osornio-Vargas A and Rowe BH: The role of socioeconomic position as an effect-modifier of the association between outdoor air pollution and children's asthma exacerbations: An equity-focused systematic review. Rev Environ Health. 31:297–309. 2016. View Article : Google Scholar : PubMed/NCBI
3	Rodrigo GJ and Plaza V: Once-daily fluticasone furoate and vilanterol for adolescents and adults with symptomatic asthma: A systematic review with meta-analysis. Ann Allergy Asthma Immunol. 116:565–570. 2016. View Article : Google Scholar : PubMed/NCBI
4	Pols DH, Wartna JB, Moed H, van Alphen EI, Bohnen AM and Bindels PJ: Atopic dermatitis, asthma and allergic rhinitis in general practice and the open population: A systematic Review. Scand J Prim Health Care. 34:143–150. 2016. View Article : Google Scholar : PubMed/NCBI
5	Paone G, Leone V, Conti V, De Marchis L, Ialleni E, Graziani C, Salducci M, Ramaccia M and Munafò G: Blood and sputum biomarkers in COPD and asthma: A review. European Rev Med Pharmacol Sci. 20:698–708. 2016.
6	Nwaru BI, McCleary N, Erkkola M, Kaila M, Virtanen SM and Sheikh A: Assisted reproductive technology and risk of asthma and allergy in the offspring: Protocol for a systematic review and meta-analysis. BMJ Open. 6:e0106972016. View Article : Google Scholar : PubMed/NCBI
7	Oh S, Ji H, Barzman D, Lin PI and Hutton J: Pediatric asthma and autism-genomic perspectives. Clin Transl Med. 4:372015. View Article : Google Scholar : PubMed/NCBI
8	Wu DJ, Hipolito E, Bilderback A, Okelo SO and Garro A: Predicting future emergency department visits and hospitalizations for asthma using the pediatric asthma control and communication instrument-emergency department version (PACCI-ED). J Asthma. 53:387–391. 2016. View Article : Google Scholar : PubMed/NCBI
9	Doymaz S, Schneider J and Sagy M: Early administration of terbutaline in severe pediatric asthma may reduce incidence of acute respiratory failure. Ann Allergy Asthma Immunol. 112:207–210. 2014. View Article : Google Scholar : PubMed/NCBI
10	Myers TR: Pediatric asthma epidemiology: Incidence, morbidity, and mortality. Respir Care Clin N Am. 6:1–14. 2000. View Article : Google Scholar : PubMed/NCBI
11	Doymaz S and Schneider J: Safety of terbutaline for treatment of acute severe pediatric asthma. Pediatr Emerg Care. Mar 8–2016.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
12	Booster GD, Oland AA and Bender BG: Psychosocial factors in severe pediatric asthma. Immunol Allergy Clin North Am. 36:449–460. 2016. View Article : Google Scholar : PubMed/NCBI
13	Idris IB, Ghazi HF, Zhie KH, Khairuman KA, Yahya SK, Abd Zaim FA, Nam CW, Rasid HZ Abdul and Isa ZM: Environmental air pollutants as risk factors for asthma among children seen in pediatric clinics in UKMMC, Kualalumpur. Annals Glob Health. 82:202–208. 2016. View Article : Google Scholar
14	Faiz A, Donovan C, Nieuwenhuis MA, van den Berge M, Postma DS, Yao S, Park CY, Hirsch R, Fredberg JJ, Tjin G, et al: Latrophilin receptors: Novel bronchodilator targets in asthma. Thorax. 72:84–82. 2017. View Article : Google Scholar
15	Volynski KE, Silva JP, Lelianova VG, Rahman M Atiqur, Hopkins C and Ushkaryov YA: Latrophilin fragments behave as independent proteins that associate and signal on binding of LTX(N4C). EMBO J. 23:4423–4433. 2004. View Article : Google Scholar : PubMed/NCBI
16	Gao GX, Li QM and Shen HH: Effect of astragali-cordyceps mixtura on TGF-beta/Smad signal pathway in the lung of asthma airway remodeling. J Ethnopharmacol. 125:68–74. 2009. View Article : Google Scholar : PubMed/NCBI
17	Li CC, Lin L, Wang XL, Guan XJ, Su MS, Xiang QW, Han H, Zhang WX and Li MR: Role of c-Jun N-terminal kinase signal transduction pathway in the course of airway remodeling of asthma rat. Zhonghua er ke za zhi. Zhonghua Er Ke Za Zhi. 46:535–539. 2008.(In Chinese).
18	Xie M, Liu XS, Xu YJ, Zhang ZX, Bai J, Ni W and Chen SX: Role of the extracellular signal-regulated kinase 1/2 signaling pathway in regulating the secretion of bronchial smooth muscle cells in a rat model of chronic asthma. Chin Med J (Engl). 121:73–77. 2008.PubMed/NCBI
19	Caminha GP, Junior JT Melo, Hopkins C, Pizzichini E and Pizzichini MM: SNOT-22: Psychometric properties and cross-cultural adaptation into the Portuguese language spoken in Brazil. Braz J Otorhinolaryngol. 78:34–39. 2012. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) methods. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Janockova J, Zilecka E, Kasparkova J, Brabec V, Soukup O, Kuca K and Kozurkova M: Assessment of DNA-binding affinity of cholinesterase reactivators and electrophoretic determination of their effect on topoisomerase I and II activity. Mol Biosyst. 12:2910–2920. 2016. View Article : Google Scholar : PubMed/NCBI
22	Rudmik L, Soler ZM, Mace JC, DeConde AS, Schlosser RJ and Smith TL: Using preoperative SNOT-22 score to inform patient decision for Endoscopic sinus surgery. Laryngoscope. 125:1517–1522. 2015. View Article : Google Scholar : PubMed/NCBI
23	Huang J, Chen Y, Long Z, Zhou X and Shu J: Clinical efficacy of tiotropium in children with asthma. Pak J Med Sci. 32:462–465. 2016.PubMed/NCBI
24	Diaz I and Mateu E: Use of ELISPOT and ELISA to evaluate IFN-gamma, IL-10 and IL-4 responses in conventional pigs. Vet Immunol Immunopathol. 106:107–112. 2005. View Article : Google Scholar : PubMed/NCBI
25	Mehravi B, Alizadeh AM, Khodayari S, Khodayari H, Ashtari K, Mohseni M, Anaraki NI, Dana EA, Safari S and Amanlou M: Acute toxicity evaluation of glycosylated Gd3+-based silica nanoprobe. Mol Imaging Biol. 19:522–530. 2017. View Article : Google Scholar : PubMed/NCBI
26	Kim SP, Lee SJ, Nam SH and Friedman M: Elm Tree (Ulmus parvifolia) Bark Bioprocessed with Mycelia of Shiitake (Lentinus edodes) Mushrooms in Liquid Culture: Composition and mechanism of protection against allergic asthma in mice. J Agric Food Chem. 64:773–784. 2016. View Article : Google Scholar : PubMed/NCBI
27	Bardin P, Kanniess F, Gauvreau G, Bredenbroker D and Rabe KF: Roflumilast for asthma: Efficacy findings in mechanism of action studies. Pulm Pharmacol Ther. 35 Suppl:S4–S10. 2015. View Article : Google Scholar : PubMed/NCBI
28	Johnathan M, Gan SH, Ezumi MF, Faezahtul AH and Nurul AA: Phytochemical profiles and inhibitory effects of Tiger Milk mushroom (Lignosus rhinocerus) extract on ovalbumin-induced airway inflammation in a rodent model of asthma. BMC Complement Altern Med. 16:1672016. View Article : Google Scholar : PubMed/NCBI
29	de Araujo CC, Marques PS, Silva JD, Samary CS, da Silva AL, Henriques I, Antunes MA, de Oliveira MV, Goldenberg RC, Morales MM, et al: Regular and moderate aerobic training before allergic asthma induction reduces lung inflammation and remodeling. Scand J Med Sci Sports. 26:1360–1372. 2016. View Article : Google Scholar : PubMed/NCBI
30	Phillips JE, Renteria L, Burns L, Harris P, Peng R, Bauer CM, Laine D and Stevenson CS: Btk inhibitor RN983 delivered by dry powder nose-only aerosol inhalation inhibits bronchoconstriction and pulmonary inflammation in the ovalbumin allergic mouse model of asthma. J Aerosol Med Pulm Drug Deliv. 29:233–241. 2016. View Article : Google Scholar : PubMed/NCBI
31	Li Z, Zheng J, Zhang N and Li C: Berberine improves airway inflammation and inhibits NF-κB signaling pathway in an ovalbumin-induced rat model of asthma. J Asthma. 53:999–1005. 2016. View Article : Google Scholar : PubMed/NCBI
32	Choudhry Z, Sengupta SM, Grizenko N, Fortier ME, Thakur GA, Bellingham J and Joober R: LPHN3 and attention-deficit/hyperactivity disorder: Interaction with maternal stress during pregnancy. J Child Psychol Psychiatry. 53:892–902. 2012. View Article : Google Scholar : PubMed/NCBI
33	Tobaben S, Sudhof TC and Stahl B: Genetic analysis of alpha-latrotoxin receptors reveals functional interdependence of CIRL/latrophilin 1 and neurexin 1 alpha. J Biol Chem. 277:6359–6365. 2002. View Article : Google Scholar : PubMed/NCBI
34	Vanders RL, Gibson PG, Wark PA and Murphy VE: Alterations in inflammatory, antiviral and regulatory cytokine responses in peripheral blood mononuclear cells from pregnant women with asthma. Respirology. 18:827–833. 2013. View Article : Google Scholar : PubMed/NCBI
35	Mauffray M, Domingues O, Hentges F, Zimmer J, Hanau D and Michel T: Neurturin influences inflammatory responses and airway remodeling in different mouse asthma models. J Immunol. 194:1423–1433. 2015. View Article : Google Scholar : PubMed/NCBI
36	Vanoirbeek JA, De Vooght V, Nemery B and Hoet PH: Multiple challenges in a mouse model of chemical-induced asthma lead to tolerance: Ventilatory and inflammatory responses are blunted, immunologic humoral responses are not. Toxicology. 257:144–152. 2009. View Article : Google Scholar : PubMed/NCBI
37	Lim Y, Vasu VT, Valacchi G, Leonard S, Aung HH, Schock BC, Kenyon NJ, Li CS, Traber MG and Cross CE: Severe vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model. Free Radical Res. 42:387–396. 2008. View Article : Google Scholar
38	Bhandari V, Choo-Wing R, Chapoval SP, Lee CG, Tang C, Kim YK, Ma B, Baluk P, Lin MI and McDonald DM: Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc Natl Acad Sci USA. 103:pp. 11021–11026. 2006; View Article : Google Scholar : PubMed/NCBI
39	Gaga M, Zervas E and Loukides S: The usefulness of inflammatory markers in monitoring treatment responses in asthma. Clin Exp Allergy. 33:855–858. 2003. View Article : Google Scholar : PubMed/NCBI
40	Boulay ME and Boulet LP: Lower airway inflammatory responses to repeated very-low-dose allergen challenge in allergic rhinitis and asthma. Clin Exp Allergy. 32:1441–1447. 2002. View Article : Google Scholar : PubMed/NCBI
41	Foster PS, Ming Y, Matthei KI, Young IG, Temelkovski J and Kumar RK: Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma. Lab Invest. 80:655–662. 2000. View Article : Google Scholar : PubMed/NCBI
42	Provotorov VM, Budnevsky AV and Filatova YI: Clinical manifestations of asthma during combination therapy using ceruloplasmin. Ter Arkh. 88:36–39. 2016.(In Russian). View Article : Google Scholar : PubMed/NCBI
43	Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, Matito A, Broesby-Olsen S, Siebenhaar F, Lange M, et al: Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 137:35–45. 2016. View Article : Google Scholar : PubMed/NCBI
44	Ghaffari J, Hossiani R Farid, Khalilian A, Nahanmoghadam N, Salehifar E and Rafatpanah H: Vitamin e supplementation, lung functions and clinical manifestations in children with moderate asthma: A randomized double blind placebo-controlled trial. Iran J Allergy Asthma Immunol. 13:98–103. 2014.PubMed/NCBI
45	García-Martín E, García-Menaya J, Sánchez B, Martínez C, Rosendo R and Agúndez JA: Polymorphisms of histamine-metabolizing enzymes and clinical manifestations of asthma and allergic rhinitis. Clin Exp Allergy. 37:1175–1182. 2007. View Article : Google Scholar : PubMed/NCBI
46	Kim TB, Kim YK, Chang YS, Kim SH, Hong SC, Jee YK, Cho SH, Min KU and Kim YY: Association between sensitization to outdoor spider mites and clinical manifestations of asthma and rhinitis in the general population of adults. J Korean Med Sci. 21:247–252. 2006. View Article : Google Scholar : PubMed/NCBI
47	Araujo MI and de Carvalho EM: Human schistosomiasis decreases immune responses to allergens and clinical manifestations of asthma. Chem Immunol Allergy. 90:29–44. 2006.PubMed/NCBI
48	Khamidova ZN: Clinical manifestations and a course of bronchial asthma complicated by gastroduodenal pathology. Probl Tuberk. 44–45. 2002.(In Russian). PubMed/NCBI
49	Zhou Y, Wang GF, Yang L, Liu F, Kang JQ, Wang RL, Gu W and Wang CY: Treatment with 1,25(OH)2D3 induced HDAC2 expression and reduced NF-κB p65 expression in a rat model of OVA-induced asthma. Braz J Med Biol Res. 48:654–664. 2015. View Article : Google Scholar : PubMed/NCBI
50	Pan C and Dong Z: Antiasthmatic Effects of Eugenol in a Mouse Model of Allergic Asthma by Regulation of Vitamin D3 Upregulated Protein 1/NF-κB Pathway. Inflammation. 38:1385–1393. 2015. View Article : Google Scholar : PubMed/NCBI
51	Garcia-Garcia FJ, Mullol J, Perez-Gonzalez M, Pujols L, Alobid I, Roca-Ferrer J and Picado C: Signal transduction pathways (MAPKs, NF-κB, and C/EBP) regulating COX-2 expression in nasal fibroblasts from asthma patients with aspirin intolerance. PLoS One. 7:e512812012. View Article : Google Scholar : PubMed/NCBI
52	Shimizu K, Konno S, Ozaki M, Umezawa K, Yamashita K, Todo S and Nishimura M: Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma. Clin Exp Allergy. 42:1273–1281. 2012. View Article : Google Scholar : PubMed/NCBI
53	Lim JC, Goh FY, Sagineedu SR, Yong AC, Sidik SM, Lajis NH, Wong WS and Stanslas J: A semisynthetic diterpenoid lactone inhibits NF-κB signalling to ameliorate inflammation and airway hyperresponsiveness in a mouse asthma model. Toxicol Appl Pharmacol. 302:10–22. 2016. View Article : Google Scholar : PubMed/NCBI