Chromofungin regulates autophagy flux to improve lung tissue inflammation in septic mice

Shengnan KANG; Shuke LIU; Xian LIU; Fenglin WANG; Wushuang ZHOU; Xiaoying CHEN; Dan ZHANG

doi:10.16016/j.1000-5404.202102051

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Chromofungin regulates autophagy flux to improve lung tissue inflammation in septic mice

Basic Medicine | 更新时间：2026-01-09

- Chromofungin regulates autophagy flux to improve lung tissue inflammation in septic mice
- Journal of Third Military Medical University Vol. 43, Issue 14, Pages: 1332-1338(2021)
- 作者机构：
  
  1.400016 重庆，重庆医科大学附属第一医院急诊&重症医学科
  2.400030 重庆，重庆市肿瘤医院
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81372102);the General Program of Natural Science Foundation of Chongqing(cstc2020jcyj-msxmX0922)
- DOI：10.16016/j.1000-5404.202102051
  CLC： R341;R563;R631.06
- Received：08 February 2021，
  
  Revised：2021-03-31，
  
  Published：30 July 2021
- 稿件说明：
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Shengnan KANG, Shuke LIU, Xian LIU, et al. Chromofungin regulates autophagy flux to improve lung tissue inflammation in septic mice[J]. Journal of Third Military Medical University, 2021, 43(14): 1332-1338.
DOI：

Shengnan KANG, Shuke LIU, Xian LIU, et al. Chromofungin regulates autophagy flux to improve lung tissue inflammation in septic mice[J]. Journal of Third Military Medical University, 2021, 43(14): 1332-1338. DOI： 10.16016/j.1000-5404.202102051.

摘要

目的

探讨嗜铬粒蛋白A衍生多肽CGA

47-66

hromofungin，CHR)在脓毒症小鼠肺组织中对自噬流的调控作用，及其对肺组织炎症损伤的影响。

方法

以C57BL/6小鼠为研究对象，通过腹腔注射脂多糖LPS(10 mg/kg)建立脓毒症小鼠急性肺损伤模型。为研究CHR对自噬的影响，在予以LPS 30 min前，先分别用CHR、自噬诱导剂雷帕霉素(Rapa)预处理小鼠，观察小鼠肺组织病理改变，进行肺泡灌洗检测炎症因子水平，Western blot和免疫荧光检测肺组织自噬标志物LC3、P62、Agt7蛋白表达，透射电镜观察自噬小体形成情况。

结果

与LPS组相比，CHR预处理可以使LPS引起的小鼠肺组织病理损伤明显减轻，同时CHR预处理可以降低小鼠肺泡灌洗液中促炎因子表达水平，增高抗炎因子表达水平(

0.05)。Western blot和免疫荧光检测都提示经CHR预处理后，自噬标志蛋白表达量升高，自噬底物蛋白表达量降低(

0.05)。电镜检查结果显示CHR预处理组中发现自噬小体及自噬溶酶体的形成，与Rapa预处理组中自噬流变化、炎症介质水平改变及肺组织病理情况等结果基本一致。

结论

CHR可能通过调控LPS刺激后肺组织中自噬流增加和炎症反应降低，对脓毒症小鼠起到肺保护作用。

Abstract

Objective

To investigate the regulative role of chromogranin A derived polypeptide CGA

47-66

(chromofungin

CHR) on autophagy flux and determine its effect on inflammatory injury in the lung tissue of septic mice.

Methods

C57BL/6 mice were inflicted by intraperitoneal administration of 10 mg/kg lipopolysaccharide to establish a mouse septic model of acute lung injury. To determine the effect of CHR on autophagy

the mice were pretreated with CHR and autophagy inducer rapamycin (Rapa) respectively in 30 min before LPS administration. The pathological changes of lung tissue in mice were observed

contents of inflammatory factors in alveolar lavage were measured

expression of autophagy-related markers LC3

P62 and Agt7 in lung tissues were determined by Western blotting and immunofluorescence assay

and formation of autophagosomes was observed by transmission electron microscopy.

Results

Compare with the LPS group

CHR pretreatment significantly attenuated LPS-induced lung pathological damages

and inhibited the expression of pro-inflammatory factors and enhanced the expression of anti-inflammatory factors in bronchoalveolar lavage fluid of mice (

0.05). The res

ults of Western blotting and immunofluorescence assay showed that the expression of autophagy marker proteins were up-regulated and the expression of autophagy substrate protein was down-regulated in the lung tissues after CHR pretreatmnet (

0.05). Transmission electron microscopy displayed autophagosomes and autophagosolysosomes were formed in the CHR pretreatment group. The changes of autophagy flux

inflammatory mediators and lung pathology were consistent with the results in the Rapa group.

Conclusion

CHR may attenuate the inflammatory response by regulating the increase of autophagy flux in lung tissue after LPS stimulation and play a protective role in the lung of septic mice.

关键词

Keywords

references

GOTTS J E, MATTHAY M A. Sepsis: pathophysiology and clinical management[J]. BMJ, 2016, 353: i1585. DOI:10.1136/bmj.i1585.

MO Y, LOU Y Y, ZHANG A Q, et al . PICK1 deficiency induces autophagy dysfunction via lysosomal impairment and amplifies sepsis-induced acute lung injury[J ] . Mediat Inflamm, 2018, 2018: 6757368. DOI:10.1155/2018/6757368.eCollection 2018..

ZHAO H Y, CHEN H G, MENG X Y, et al . Autophagy activation improves lung injury and inflammation in sepsis[J ] . Inflammation, 2019, 42(2): 426-439. DOI:10.1007/s10753- 018-00952-5.

QIN L, LI M, TAN H L, et al . Mechanistic target of rapamycin-mediated autophagy is involved in the alleviation of lipopolysaccharide-induced acute lung injury in rats[J ] . Int Immunopharmacol, 2020, 78: 105790. DOI:10.1016/j.intimp. 2019.105790.

BODAS M, PEHOTE G, SILVERBERG D, et al . Autophagy augmentation alleviates cigarette smoke-induced CFTR-dysfunction, ceramide-accumulation and COPD-emphysema pathogenesis[J ] . Free Radic Biol Med, 2019, 131: 81-97. DOI:10.1016/j.freeradbiomed.2018.11. 023.

KESIREDDY V S, CHILLAPPAGARI S, AHUJA S, et al . Susceptibility of microtubule-associated protein 1 light chain 3β (MAP1LC3B/LC3B) knockout mice to lung injury and fibrosis[J ] . Faseb J, 2019, 33(11): 12392-12408. DOI:10.1096/fj.201900854R.

WANG Z X, LI Y, YANG X W, et al . Protective effects of rapamycin induced autophagy on CLP septic mice[J ] . Comp Immunol Microbiol Infect Dis, 2019, 64: 47-52. DOI:10.1016/j.cimid.2019.01.009.

YEN Y T, YANG H R, LO H C, et al . Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury[J ] . Surg U S, 2013, 153(5): 689-698.

ZHANG D,SHOOSHTARIZADEH P, LAVENTIE B J, et al . Two chromogranin a-derived peptides induce calcium entry in human neutrophils by calmodulin-regulated calcium independent phospholipase A2[J ] . PLoS ONE, 2009, 4(2): e4501. DOI:10.1371/journal.pone.0004501.

EISSA N, HUSSEIN H, KERMARREC L, et al . Chromofungin ameliorates the progression of colitis by regulating alternatively activated macrophages[J ] . Front Immunol, 2017, 8: 1131. DOI:10.3389/fimmu.2017.01131.

刘疏柯, 姜丽萍, 刘贤, 等. CGA衍生多肽CHR通过调控自噬流减轻脂多糖诱导的小鼠肺损伤[J]. 重庆医科大学学报. 2020, 45(6): 731-736. DOI:10.13406/j.cnki.cyxb.002203.

LIUS K, JIANG L P, LIU X, et al . Chromogranin a-derived polypeptide CHR alleviates lipopolysaccharide induced lung injury in mice by regulating autophagy flux[J ] . J Chongqing Med Univ, 2020, 45(6): 731-736. DOI:10.13406/j.cnki.cyxb. 002203.

LUO L, LIU S Y, ZHANG D, et al . Chromogranin A (CGA)-derived polypeptide (CGA 47-66) inhibits TNF-α-induced vascular endothelial hyper-permeability through SOC-related Ca 2+ signaling[J ] . Peptides, 2020, 131: 170297. DOI:10.1016/j.peptides.2020.170297..

PASSMORE M R, BYRNE L, OBONYO N G, et al . Inflammation and lung injury in an ovine model of fluid resuscitated endotoxemic shock[J ] . Respir Res, 2018, 19(1): 231. DOI:10.1186/s12931-018-0935-4.

TAKAHASHI W, WATANABE E, FUJIMURA L, et al . Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis[J ] . Crit Care Lond Engl, 2013, 17(4): R160. DOI:10.1186/cc12839.

HU Y, LOU J, MAO Y Y, et al . Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury[J ] . Autophagy, 2016, 1 2(12): 2286-2299. DOI:10.1080/15548627.2016.1230584.

ZHANG Y, LIU G J, DULL R O, et al . Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation[J ] . Am J Physiol Lung Cell Mol Physiol, 2014, 307(2): L173-L185. DOI:10.1152/ajplung.00083.2014..

LIN L, ZHANG L J, YU L Z, et al . Time-dependent changes of autophagy and apoptosis in lipopolysaccharide-induced rat acute lung injury[J ] . Iran J Basic Med Sci, 2016, 19(6): 632-637.

LEI M, WANG C J, YU F, et al . Different intensity of autophagy regulate interleukin-33 to control the uncontrolled inflammation of acute lung injury[J ] . Inflamm Res, 2019, 68(8): 665-675. DOI:10.1007/s00011-019-01250-y.

LIN C W, LO S, PERNG D S, et al . Complete activation of autophagic process attenuates liver injury and improves survival in septic mice[J ] . Shock, 2014, 41(3): 241-249. DOI:10.1097/SHK.0000000000000111.

ZENG M C, SANG W H, CHEN S, et al . 4-PBA inhibits LPS-induced inflammation through regulating ER stress and autophagy in acute lung injury models[J ] . Toxicol Lett, 2017, 271: 26-37. DOI:10.1016/j.toxlet.2017.02.023.

GAO Y, WANG N, LI R H, et al . The role of autophagy and the chemokine (C-X-C motif) ligand 16 during acute lung injury in mice[J ] . Med Sci Monit, 2018, 24: 2404-2412. DOI:10.12659/msm.906016.

HSU C H, REYES L F, ORIHUELA C J, et al . Chromogranin A levels and mortality in patients with severe sepsis[J ] . Biomarkers, 2015, 20(3): 171-176. DOI:10.3109/1354750X.2015.1046932.

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