, Volume 27, Issue 1, pp 99–107 | Cite as

SB203580 attenuates acute lung injury and inflammation in rats with acute pancreatitis in pregnancy

  • Yu Zhou
  • Hongmiao Xia
  • Liang Zhao
  • Fangchao Mei
  • Man Li
  • Yundong You
  • Kailiang Zhao
  • Weixing WangEmail author
Original Article


Acute pancreatitis in pregnancy (APIP) can lead to multiple maternal and fetal organ injury and mitogen-activated protein kinase (MAPK) signaling pathway may be involved in it; however, whether APIP can result in acute lung injury and P38MAPK signaling pathway is involved in the pathogenesis has not been elucidated. The present study was undertaken to investigate the participation of P38MAPK signaling pathway and the protective effect of SB203580, an inhibitor of P38MAPK on acute lung injury induced by APIP. Twenty-four late-gestation SD rats were randomly assigned to four groups: Sham operation (SO) group, SB302580 (SB) group, APIP group, and SB + APIP group. All the rats were killed 6 h after modeling. The severity of pancreatitis was evaluated by serum amylase (AMY) and lipase (LIPA) and histopathological changes. Histological assessment of the lung and inflammatory cell infiltration was performed by H&E and immunofluorescence assay. The lung wet/dry (W/D) weight ratio was determined, and the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to detect the protein expression of phosphorylated and total P38, tumor necrosis factor (TNF)-α, and intercellular adhesion molecules 1 (ICAM-1) in lung tissues. Obvious pathological changes existed in pancreas and lung after the induction of APIP, and their pathological scores were significantly higher than that of control group. The results showed that the phosphorylation of P38MAPK was elevated in the lung of APIP rats. Compared with APIP group, the intervention of SB203580 alleviated the pathological injury of the pancreas and lungs, decreased serum AMY and LIPA, attenuated the secretion of TNF-α, IL-1β, and IL-6 in lung, reduced the inflammatory cells’ infiltration and lung W/D ratio and inhibited the activation of P38MAPK signaling pathway. These results suggest that APIP can lead to acute lung injury and inflammation and SB203580 can inhibit the lung injury by inhibiting the P38MAPK signaling pathway and blocking the inflammatory responses.


P38MAPK Acute lung injury Acute pancreatitis Pregnancy Inflammatory response 



The authors are grateful to the Central Laboratory, Hubei Key Laboratory of Digestive System Disease of Renmin Hospital of Wuhan University for providing relevant experimental facilities and technical support.


This work was supported by the National Natural Science Foundation of China (No.81370562 and 81700567).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Ethics Committee of Renmin Hospital of Wuhan University (No. WDRM-20150606) and performed in compliance with the ARRIVE guidelines.


  1. Akcakaya A, Ozkan OV, Okan I, Kocaman O, Sahin M (2009) Endoscopic retrograde cholangiopancreatography during pregnancy without radiation. World J Gastroenterol 15:3649–3652CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bargagli E, Olivieri C, Nikiforakis N, Cintorino M, Magi B, Perari MG, Vagaggini C, Spina D, Prasse A, Rottoli P (2009) Analysis of macrophage migration inhibitory factor (MIF) in patients with idiopathic pulmonary fibrosis. Respir Physiol Neurobiol 167:261–267CrossRefPubMedGoogle Scholar
  3. Cha SM, Cha JD, Jang EJ, Kim GU, Lee KY (2016) Sophoraflavanone G prevents Streptococcus mutans surface antigen I/II-induced production of NO and PGE2 by inhibiting MAPK-mediated pathways in RAW 264.7 macrophages. Arch Oral Biol 68:97–104CrossRefPubMedGoogle Scholar
  4. Chen Y, Wang L, Kang Q, Zhang X, Yu G, Wan X, Wang J, Zhu K (2017) Heat shock protein A12B protects vascular endothelial cells against sepsis-induced acute lung injury in mice. Cell Physiol Biochem 42:156–168CrossRefPubMedGoogle Scholar
  5. Cornell TT, Fleszar A, McHugh W, Blatt NB, Le Vine AM, Shanley TP (2012) Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury. Am J Physiol Lung Cell Mol Physiol 303:L251–L258CrossRefPubMedPubMedCentralGoogle Scholar
  6. Ducarme G, Maire F, Chatel P, Luton D, Hammel P (2014) Acute pancreatitis during pregnancy: a review. J Perinatol 34:87–94CrossRefPubMedGoogle Scholar
  7. Geng Y, Li W, Sun L, Tong Z, Li N, Li J (2011) Severe acute pancreatitis during pregnancy: eleven yearsexperience from a surgical intensive care unit. Dig Dis Sci 56:3672–3677CrossRefPubMedGoogle Scholar
  8. Guo ZD, Zhao L, Wang P, Deng WH, Shi Q, Zuo T, Hong YP, Wang WX (2018) Fetal liver injury ameliorated by migration inhibitory factor inhibition in a rat model of acute pancreatitis in pregnancy. J Obstet Gynaecol Res 44:374–383CrossRefPubMedGoogle Scholar
  9. Hacker FM, Whalen PS, Lee VR, Caughey AB (2015) Maternal and fetal outcomes of pancreatitis in pregnancy. Am J Obstet Gynecol 213:568.e1–568.e5CrossRefGoogle Scholar
  10. Han HJ, Li M, Son JK, Seo CS, Song SW, Kwak SH, Bae HB (2013) Sauchinone, a lignan from Saururus chinensis, attenuates neutrophil pro-inflammatory activity and acute lung injury. Int Immunopharmacol 17:471–477CrossRefPubMedGoogle Scholar
  11. Heinrichs D, Knauel M, Offermanns C, Berres ML, Nellen A, Leng L, Schmitz P, Bucala R, Trautwein C, Weber C, Bernhagen J, Wasmuth HE (2011) Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74. Proc Natl Acad Sci USA 108:17444–17449CrossRefPubMedGoogle Scholar
  12. Hernandez A, Petrov MS, Brooks DC, Banks PA, Ashley SW, Tavakkolizadeh A (2007) Acute pancreatitis and pregnancy: a 10-year single center experience. J Gastrointest Surg 11:1623–1627CrossRefPubMedGoogle Scholar
  13. Huang W, Cane MC, Mukherjee R, Szatmary P, Zhang X, Elliott V, Ouyang Y, Chvanov M, Latawiec D, Wen L, Booth DM, Haynes AC, Petersen OH, Tepikin AV, Criddle DN, Sutton R (2017) Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release. Gut 66:301–313CrossRefPubMedGoogle Scholar
  14. Hung YC, Hsu CC, Chung CH, Huang TF (2016) The disintegrin, trimucrin, suppresses LPS-induced activation of phagocytes primarily through blockade of NF-kappaB and MAPK activation. Naunyn Schmiedebergs Arch Pharmacol 389:723–737CrossRefPubMedGoogle Scholar
  15. Kong G, Huang X, Wang L, Li Y, Sun T, Han S, Zhu W, Ma M, Xu H, Li J, Zhang X, Liu X, Wang X (2016) Astilbin alleviates LPS-induced ARDS by suppressing MAPK signaling pathway and protecting pulmonary endothelial glycocalyx. Int Immunopharmacol 36:51–58CrossRefPubMedGoogle Scholar
  16. Lankisch PG, Apte M, Banks PA (2015) Acute pancreatitis. Lancet 386:85–96CrossRefPubMedGoogle Scholar
  17. Mali P (2016) Pancreatitis in pregnancy: etiology, diagnosis, treatment, and outcomes. Hepatobiliary Pancreat Dis Int 15:434–438CrossRefPubMedGoogle Scholar
  18. Mei F, Zuo T, Zhao L, Shi Q, Xiang M, Hong Y, Li M, Wang W (2018) Differential JNK, p38 and ERK response to renal injury in a rat model of acute pancreatitis in pregnancy. Arch Gynecol Obstet 297:933–942CrossRefPubMedGoogle Scholar
  19. Mo LQ, Chen Y, Song L, Wu GM, Tang N, Zhang YY, Wang XB, Liu KX, Zhou J (2014) Osthole prevents intestinal ischemia-reperfusion-induced lung injury in a rodent model. J Surg Res 189:285–294CrossRefPubMedGoogle Scholar
  20. Mole DJ, Webster SP, Uings I, Zheng X, Binnie M, Wilson K, Hutchinson JP, Mirguet O, Walker A, Beaufils B, Ancellin N, Trottet L, Beneton V, Mowat CG, Wilkinson M, Rowland P, Haslam C, McBride A, Homer NZ, Baily JE, Sharp MG, Garden OJ, Hughes J, Howie SE, Holmes DS, Liddle J, Iredale JP (2016) Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. Nat Med 22:202–209CrossRefPubMedPubMedCentralGoogle Scholar
  21. Pan Y, Li Y, Gao L, Tong Z, Ye B, Liu S, Li B, Chen Y, Yang Q, Meng L, Wang Y, Liu G, Lu G, Li W, Li J (2017) Development of a novel model of hypertriglyceridemic acute pancreatitis in mice. Sci Rep 7:40799CrossRefPubMedPubMedCentralGoogle Scholar
  22. Roger T, Schneider A, Weier M, Sweep FC, Le Roy D, Bernhagen J, Calandra T, Giannoni E (2016) High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates. Proc Natl Acad Sci USA 113:E997–E1005CrossRefPubMedGoogle Scholar
  23. Russell KE, Chung KF, Clarke CJ, Durham AL, Mallia P, Footitt J, Johnston SL, Barnes PJ, Hall SR, Simpson KD, Starkey MR, Hansbro PM, Adcock IM, Wiegman CH (2016) The MIF antagonist ISO-1 attenuates corticosteroid-insensitive inflammation and airways hyperresponsiveness in an ozone-induced model of COPD. PLoS One 11:e0146102CrossRefPubMedPubMedCentralGoogle Scholar
  24. Sendler M, Weiss FU, Golchert J, Homuth G, van den Brandt C, Mahajan UM, Partecke LI, Doring P, Gukovsky I, Gukovskaya AS, Wagh PR, Lerch MM, Mayerle J (2018) Cathepsin B-mediated activation of trypsinogen in endocytosing macrophages increases severity of pancreatitis in mice. Gastroenterology 154:704–718.e10CrossRefPubMedPubMedCentralGoogle Scholar
  25. Weaver LC, Bao F, Dekaban GA, Hryciw T, Shultz SR, Cain DP, Brown A (2015) CD11d integrin blockade reduces the systemic inflammatory response syndrome after traumatic brain injury in rats. Exp Neurol 271:409–422CrossRefPubMedPubMedCentralGoogle Scholar
  26. Wu BU, Banks PA (2013) Clinical management of patients with acute pancreatitis. Gastroenterology 144:1272–1281CrossRefPubMedGoogle Scholar
  27. Zhang Y, Xu T, Wu B, Chen H, Pan Z, Huang Y, Mei L, Dai Y, Liu X, Shan X, Liang G (2017) Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury. J Cell Mol Med 21:746–757CrossRefPubMedGoogle Scholar
  28. Zhao L, Zuo T, Shi Q, Mei FC, Hong YP, Deng WH, Yu J, Hu P, Wang WX (2017) A preliminary study on fetal lung injury in a rat model of acute pancreatitis in pregnancy. Pathol Res Pract 213:1370–1377CrossRefPubMedGoogle Scholar
  29. Zhou Z, Zhu X, Chen J, Yang S, Sun R, Yang G (2014) The interaction between Toll-like receptor 4 signaling pathway and hypoxia-inducible factor 1alpha in lung ischemia-reperfusion injury. J Surg Res 188:290–297CrossRefPubMedGoogle Scholar
  30. Zhou Y, Zhao L, Mei F, Hong Y, Xia H, Zuo T, Ding Y, Wang W (2018) Macrophage migration inhibitory factor antagonist (S, R)3(4hydroxyphenyl)4,5dihydro5isoxazole acetic acid methyl ester attenuates inflammation and lung injury in rats with acute pancreatitis in pregnancy. Mol Med Rep 17:6576–6584PubMedPubMedCentralGoogle Scholar
  31. Zou R, Wang MH, Chen Y, Fan X, Yang B, Du J, Wang XB, Liu KX, Zhou J (2018) Hydrogen-rich saline attenuates acute lung injury induced by limb ischemia/reperfusion via down-regulating chemerin and NLRP3 in rats. Shock. CrossRefPubMedGoogle Scholar
  32. Zuo T, Yu J, Wang WX, Zhao KL, Chen C, Deng WH, He XB, Wang P, Shi Q, Guo WY (2016) Mitogen-activated protein kinases are activated in placental injury in rat model of acute pancreatitis in pregnancy. Pancreas 45:850–857CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of General SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
  2. 2.Medical Examination CenterRenmin Hospital of Wuhan UniversityWuhanChina
  3. 3.Central LaboratoryRenmin Hospital of Wuhan UniversityWuhanChina
  4. 4.Hubei Key Laboratory of Digestive System DiseaseRenmin Hospital of Wuhan UniversityWuhanChina

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