Substance P attenuates hyperoxia‑induced lung injury in neonatal rats

Yang,Lin; Liu,Cong; Dang,Hongxing; Fang,Fang; Tan,Lingping; Zhao,Ping; Xu,Feng; Liu,Chenjun

doi:10.3892/mmr.2013.1809

Substance P attenuates hyperoxia‑induced lung injury in neonatal rats

Authors:
- Lin Yang
- Cong Liu
- Hongxing Dang
- Fang Fang
- Lingping Tan
- Ping Zhao
- Feng Xu
- Chenjun Liu
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Affiliations: Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, and PICU, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
Published online on: November 18, 2013 https://doi.org/10.3892/mmr.2013.1809
Pages: 595-599

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Abstract

The aim of the study was to investigate the effects of substance P (SP) in hyperoxia‑induced lung injury in newborn rats and to elucidate its protective mechanism of action via the sonic hedgehog (SHH) signaling pathway. Twelve‑hour‑old neonatal Sprague‑Dawley rats were randomly divided into one of four groups: air, hyperoxia, air + SP and hyperoxia + SP. In a separate set of experiments, the neonatal rat pups were exposed to 21 or 95% O2 for 14 days with or without intraperitoneal administration of rat SP. The animals were sacrificed at 3, 7 and 14 days, respectively, of hyperoxia exposure. Lung pathology and grade of lung tissue injury were examined by light microscopy. Oxidative stress was evaluated by malondialdehyde (MDA) and antioxidant activity was measured by superoxide dismutase (SOD) in tissue homogenates. The expression of SHH mRNA and protein were detected by quantitative polymerase chain reaction (qPCR) and western blot analysis, respectively. In the hyperoxia group, marked characteristics of acute lung injury (ALI) were observed. Compared with the simple hyperoxia treatment, the lung damage was significantly ameliorated following the addition of SP. Furthermore, the levels of MDA were decreased and SOD was significantly increased following the addition of SP. SP stimulation may result in activation of the SHH signaling pathway and the expression of SHH markedly increased following treatment with SP. The present study demonstrated that SP protected against the hyperoxia‑induced lung damage by attenuating oxidative stress, elevating the antioxidant activities and upregulating the signaling pathway of SHH.

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1	Kallet RH and Matthay MA: Hyperoxic acute lung injury. Respir Care. 58:123–141. 2013. View Article : Google Scholar
2	Buccellato LJ, Tso M, Akinci OI, Chandel NS and Budinger GR: Reactive oxygen species are required for hyperoxia-induced Bax activation and cell death in alveolar epithelial cells. J Biol Chem. 279:6753–6760. 2004. View Article : Google Scholar : PubMed/NCBI
3	Maggi CA, Giachetti A, Dey RD and Said SI: Neuropeptides as regulators of airway function: vasoactive intestinal peptide and the tachykinins. Physiol Rev. 75:277–322. 1995.PubMed/NCBI
4	Hökfelt T, Pernow B and Wahren J: Substance P: a pioneer amongst neuropeptides. J Intern Med. 249:27–40. 2001.PubMed/NCBI
5	Kim JS, Rabe KF, Magnussen H, Green JM and White SR: Migration and proliferation of guinea pig and human airway epithelial cells in response to tachykinins. Am J Physiol. 269:L119–L126. 1995.PubMed/NCBI
6	Kim JS, McKinnis VS, Adams K and White SR: Proliferation and repair of guinea pig tracheal epithelium after neuropeptide depletion and injury in vivo. Am J Physiol. 273:1235–1241. 1997.PubMed/NCBI
7	Huang B, Fu H, Yang M, Fang F, Kuang F and Xu F: Neuropeptide substance P attenuates hyperoxia-induced oxidative stress injury in type II alveolar epithelial cells via suppressing the activation of JNK pathway. Lung. 187:421–426. 2009. View Article : Google Scholar
8	Zhang M, Wang H, Teng H, Shi J and Zhang Y: Expression of SHH signaling pathway components in the developing human lung. Histochem Cell Biol. 134:327–335. 2010. View Article : Google Scholar : PubMed/NCBI
9	Li Y, Zhang H, Choi SC, Litingtung Y and Chiang C: Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis. Dev Biol. 270:214–231. 2004. View Article : Google Scholar : PubMed/NCBI
10	Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA and Baylin SB: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 422:313–317. 2003. View Article : Google Scholar : PubMed/NCBI
11	Lai K, Kaspar BK, Gage FH and Schaffer DV: Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci. 6:21–27. 2003. View Article : Google Scholar : PubMed/NCBI
12	Fu M, Lui VC, Sham MH, Pachnis V and Tam PK: Sonic hedgehog regulates the proliferation, differentiation, and migration of enteric neural crest cells in gut. J Cell Biol. 166:673–684. 2004. View Article : Google Scholar : PubMed/NCBI
13	Kinnula VL and Crapo JD: Superoxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med. 167:1600–1619. 2003. View Article : Google Scholar : PubMed/NCBI
14	Jackson RM: Pulmonary oxygen toxicity. Chest. 88:900–905. 1985. View Article : Google Scholar
15	Scott JR, Muangman P and Gibran NS: Making sense of hypertrophic scar: a role for nerves. Wound Repair Regen. 15(Suppl 1): S27–S31. 2007. View Article : Google Scholar : PubMed/NCBI
16	Scott JR, Muangman PR, Tamura RN, et al: Substance P levels and neutral endopeptidase activity in acute burn wounds and hypertrophic scar. Plast Reconstr Surg. 115:1095–1102. 2005. View Article : Google Scholar : PubMed/NCBI
17	Dib M, Zsengeller Z, Mitsialis A, Lu B, Craig S, Gerard C and Gerard NP: A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury. Am J Physiol Lung Cell Mol Physiol. 297:L687–L697. 2009. View Article : Google Scholar : PubMed/NCBI
18	Oslund KL, Hyde DM, Putney LF, et al: Activation of neurokinin-1 receptors during ozone inhalation contributes to epithelial injury and repair. Am J Respir Cell Mol Biol. 39:279–288. 2008. View Article : Google Scholar : PubMed/NCBI
19	Chen Y and Struhl G: Dual roles for patched in sequestering and transducing Hedgehog. Cell. 87:553–563. 1996. View Article : Google Scholar : PubMed/NCBI
20	Motoyama J, Liu J, Mo R, Ding Q, Post M and Hui CC: Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet. 20:54–57. 1998. View Article : Google Scholar : PubMed/NCBI
21	Le H, Kleinerman R, Lerman OZ, et al: Hedgehog signaling is essential for normal wound healing. Wound Repair Regen. 16:768–773. 2008. View Article : Google Scholar : PubMed/NCBI
22	Katoh Y and Katoh M: Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review). Int J Mol Med. 18:1019–1023. 2006.PubMed/NCBI
23	Kusano KF, Pola R, Murayama T, et al: Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling. Nat Med. 11:1197–1204. 2005. View Article : Google Scholar : PubMed/NCBI
24	Warburton D, Zhao J, Berberich MA and Bernfield M: Molecular embryology of the lung: then, now, and in the future. Am J Physiol. 276:L697–L704. 1999.PubMed/NCBI
25	Litingtung Y, Lei L, Westphal H and Chiang C: Sonic hedgehog is essential to foregut development. Nat Genet. 20:58–61. 1998. View Article : Google Scholar : PubMed/NCBI
26	Stewart GA, Hoyne GF, Ahmad SA, et al: Expression of the developmental Sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes. J Pathol. 199:488–495. 2003. View Article : Google Scholar : PubMed/NCBI