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Mucus hypersecretion in chronic obstructive pulmonary disease: From molecular mechanisms to treatment

  • Ruonan Yang , Xiaojie Wu , Abdelilah Soussi Gounni and Jungang Xie EMAIL logo
Published/Copyright: December 20, 2023
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Journal of Translational Internal Medicine
From the journal Journal of Translational Internal Medicine Volume 11 Issue 4

Introduction

Chronic obstructive pulmonary disease (COPD) is among the leading causes of mortality and morbidity worldwide, which has caused tremendous burden on society.[1,2] Mucus hypersecretion is recognized as one of the main pathophysiological changes and is associated with lung function decline, exacerbations, hospitalization and mortality in patients with COPD.[3] Exposure to cigarette smoke or other irritants promote submucosal gland hypertrophy and goblet cell metaplasia to overproduce mucus through the activation of a variety of signaling pathways. In turn, mucus accumulated in airways worsens the symptoms of airway obstruction and hypoxemia.[4] With the function of blocking specific signaling pathway, it has been identified that drugs targeting mucus hypersecretion can not only alleviate clinical symptoms but also reduce the respiratory inflammatory response in COPD.[5]

Thus, research for a better understanding about molecular mechanisms of mucus hypersecretion has become a hotspot for the treatment of COPD.

Risk factors of airway mucus hypersecretion

The most common exogenous factor that stimulates mucus hypersecretion is cigarette smoke.[6] Previous studies have shown that cigarette smoke extract (CSE) can increase the expression of mucin-5 subtype AC(MUC5AC) in a concentration-dependent manner.[7] Another common risk factor is particulate matter 2.5 (PM2.5), which can be deposited in the small airways and induce MUC5AC expression caused by oxidative stress.[8,9]

Most of endogenous factors that induce mucus hypersecretion are inflammatory mediators, including neutrophil elastase (NE),[10] interleukin-13 (IL-13),[11] interleukin- 1β (IL-1β),[12]interleukin-4 (IL-4),[13] lipopolysaccharide(LPS),[14] matrix metalloproteinase-9 (MMP-9),[15] etc. To date, NE is the most potent secretagogue.[16] NE can cleave pro-transforming growth factor (TGF)-α to release mature TGF-α, which can activate epidermal growth factor receptor (EGFR) signaling in a ligand-dependent manner. In addition, NE is locally released to induce goblet cell degranulation when neutrophils and goblet cells are in close contact.[17]

Molecular mechanisms of airway mucus hypersecretion

Signaling pathways leading to mucus overproduction

EGFR signaling pathway: EGFR is activated by exogenous reactive oxygen species (ROS) induced by cigarette smoke and endogenous ROS generated by neutrophils. The downstream of EGFR can activate the nuclear transcription factors like nuclear factor kB (NF-kB) to trigger the transcription of MUC gene.[18] Moreover, EGFR can phosphorylate signal transducer and activator of transcription 6 (STAT6), resulting in the down-regulation of forkhead box A2 (FOXA2) expression, thereby promoting the proliferation of goblet cells and the secretion of mucus.[19]

NF-kB signaling pathway: Both in vitro and in vivo, tumor necrosis factor (TNF)-α-mediated mucin production is dependent on IКB kinase (IKK) and NF-kB. NF-kB can regulate a variety of genes, including the MUC gene. Sequence analysis of the MUC2 and MUC5AC promoter clones revealed the presence of NF-kB response elements.[20] A study in mouse models of COPD has demonstrated that NF-kB is essential for mucus production.[21]

p38 mitogen-activated protein kinase (MAPK) signaling pathway: p38 kinase, a member of the MAPK family, is a highly conserved protein kinase that can be activated by many inflammatory signals. Hemophilus influenzae is a common pathogen of COPD, and studies have found that Hemophilus influenzae can upregulate MUC gene transcription through the activation of TLR2-MyD88-dependent p38 MAPK pathway.[22]

Signaling pathways leading to mucus secretion and clearance dysfunction

Myristoylated alanine-rich C kinase substrate (MARCKS) protein signaling pathway: MARCKS is a key regulatory molecule that mediates the release of mucin granules from human bronchial epithelial (HBE) cells.[23] Phosphorylation of MARCKS by protein kinase C(PKC) leads to its translocation to the cytoplasm, followed by dephosphorylation of MARCKS by protein kinase G (PKG). Dephosphorylated MARCKS can bind to the membrane of mucin granules, then MARCKS promotes the transport of mucin granules to the membrane for release.[24]

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein signaling pathway: SNARE proteins can initiate vesicle fusion, regulate intracellular membrane fusion events, and participate in the fusion of mucin particles and cell membranes. Through interacting with Ca2+ sensor and other factors, SNARE proteins mediate Ca2+-triggered mucin exocytosis.[25] Studies have shown that the most abundant SNARE protein in the airway epithelium is mainly vesicle-associated membrane protein 8 (VAMP8).[26]

Epithelial sodium channel (ENaC) signaling pathway: Airway surface hydration is mainly controlled by ENaC and cystic fibrosis transmembrane regulator (CFTR) pathways. Studies have shown that cigarette smoke-induced ROS can disrupt the function and activity of ENaC, thereby disrupting mucin hydration and reducing mucus expulsion.[27]

Ciliophagy signaling pathway: Normal ciliary structure and function help to transport the mucus from the airway to the larynx. A study has demonstrated that histone deacetylase 6 (HDAC6) and other regulators of the autophagic pathway can lead to cilia shortening and abnormal function, resulting in impaired mucociliary clearance during CS exposure.[28]

Treatment of airway mucus hypersecretion

For the above-mentioned risk factors and signaling pathways of airway mucus hypersecretion, the current treatment principles include eliminating exogenous risk factors, inhibiting mucus synthesis and secretion, promoting mucus clearance and other physical expectoration therapy.[29] It has also been summarized in the Table 1.

Table 1

Targets and relative inhibitors for the treatment of mucus hypersecretion in COPD

Target Inhibitor(s)
Smoking, PM2.5 Smoking cessation, improvement of air quality
Mucus synthesis
NE NE inhibitors, batimastat, suramin
EGFR EGFR tyrosine kinase inhibitors: AG1478, BIBX1522, ZD1839
p38 MAPK inhibitors: SB-202190
p38 MAPK NF-kB Macrolide antibiotics: erythromycin, flurythromycin
Mucus secretion
MARCKS MARCKS inhibitors: MARCKS-specific antisense oligonucleotides
SNARE SNARE protein inhibitors: EGF-LHN-C
Mucus clearance
Cholinergic pathway Mucus viscosity Expectorants: Guaifenesin, hypertonic saline
P2Y2 Mucolytics: N-Acetyl Cysteine
P2Y2 receptor agonists

  1. COPE: Chronic obstructive pulmonary disease; NE: neutrophil elastase; EGFR: epidermal growth factor receptor; MAPK: mitogen-activated protein kinase; MARCKS: myristoylated alanine-rich C kinase substrate; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; NF-kB: nuclear factor kappa B.

Elimination of exogenous risk factors

As described above, smoking and air pollution are important risk factors for COPD. Therefore, smoking cessation and improvement of air quality should be the primary measures to prevent and treat mucus hypersecretion in chronic airway inflammatory diseases.[30]

Drugs that inhibit mucus synthesis

EGFR tyrosine kinase inhibitors: Cigarette smoke, PM2.5 and oxidative stress can all stimulate EGFR activation, resulting in increased mucin secretion. It can be seen that the EGFR signaling pathway plays a central regulatory role in mucus hypersecretion. Studies have shown that pretreatment with the selective EGFR tyrosine kinase inhibitor BIBX1522 can effectively prevent the secretion of MUC5AC in asthma models and in a rat model of TNF-α-induced mucus hypersecretion.[31]

Macrolide antibiotics: Studies have shown that macrolide antibiotics can significantly reduce LPS-induced expression of MUC5AC in rat bronchi and reduce neutrophil counts as well as mucin levels in bronchoalveolar lavage fluid, which may be caused by the inactivation of NF-kB.[32] Another study has shown that macrolide antibiotics can quickly accumulate in neutrophils and macrophages, thus inhibiting the secretion of NE and mucus secretion.[33]

NE inhibitors: Studies have shown that the NE inhibitor ONO-5046 can reverse ozone-induced mucus hypersecretion and neutrophil aggregation in guinea pig models.[34] The selective NE inhibitor ICI2000355 has also been shown to reverse mucus hypersecretion induced by ovalbumin sensitization in guinea pig models.[35]

p38 MAPK inhibitors: Administration of the p38 MAPK inhibitor (SB-202190) significantly improved IL-13-induced goblet cell hyperplasia in vitro.[36]

Drugs that inhibit mucus secretion

MARCKS inhibitors: As previously mentioned, MARCKS mediates the intracellular movement and exocytosis of mucin particles.[24] Studies have shown that MARCKS-specific antisense oligonucleotides can downregulate MARCKS levels in HBE cells and significantly attenuate PKC/PKG activation-induced mucin secretion.[37]

SNARE protein inhibitors: SNARE protein inhibitor (EGF-LHN-C) inhibits mucin secretion by inhibiting the fusion of mucin granules with the cell membrane.[38]

Drugs that promote mucus clearance

Expectorants: Expectorants can stimulate the cholinergic pathway and increase the secretion of serous fluid from the bronchial submucosal glands to reduce mucus viscosity, resulting in promotion of mucus clearance.[39]

Mucolytics: With the characteristics of reducing mucus viscosity, mucolytics are the most widely used drugs for the treatment of mucus hypersecretion. For example, N-Acetyl Cysteine (NAC) can break disulphide bonds linking mucin polymers to reduce the viscosity of mucus.[40]

Purinergic receptor P2Y, G-protein coupled, 2 (P2Y2) receptor agonists: Studies have shown that the efficiency of P2Y2 receptor agonists to increase airway mucus clearance is significantly greater than that of hypertonic saline solution, which may be related to the increase of water secretion and ciliary beating frequency by P2Y2 receptor agonists.[41]

In addition to the above drug treatment, the symptoms of patients can be alleviated to a certain extent through autogenic drainage,[42] high-frequency chest wall oscillation (HFCWO)[43] and bronchoscopic treatment.[44]

Summary

So far, some progress has been made in the molecular mechanisms and drug treatment of mucus hypersecretion in COPD. A variety of drugs have been found to have certain therapeutic effects on mucus hypersecretion. However, most of the above drugs are still in the experimental research stage and there is still a long way to go before they can be used in clinical treatment. Further investigation is urgently needed to develop understanding and therapies for airway mucus hypersecretion in COPD.

Prof. Jungang Xie, Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.

Funding statement: This study was supported by the National Natural Science Foundation of China (No., 82170049, 81973986), Health Research Fund of Wuhan (No. WX21Q07) and Leading talents of public health in Hubei Province (2022SCZ047).

  1. Conflicts of Interest

    The authors declare that there is no conflict of interest.

References

1 Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med 2017;5:691–706.Search in Google Scholar

2 Labaki WW, Rosenberg SR. Chronic Obstructive Pulmonary Disease. Ann Intern Med 2020;173:ITC17–32.10.7326/IsTranslatedFrom_AITC202008040_JapaneseSearch in Google Scholar PubMed

3 Martin C, Frija-Masson J, Burgel P-R. Targeting mucus hypersecretion: new therapeutic opportunities for COPD? Drugs 2014;74:1073–89.10.1007/s40265-014-0235-3Search in Google Scholar PubMed

4 Dunican EM, Elicker BM, Henry T, Gierada DS, Schiebler ML, Anderson W, et al. Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers. Am J Respir Crit Care Med 2021;203:957–68.10.1164/rccm.202006-2248OCSearch in Google Scholar PubMed PubMed Central

5 Vestbo J, Hogg JC. Convergence of the epidemiology and pathology of COPD. Thorax 2006;61:86–8.10.1136/thx.2005.046227Search in Google Scholar PubMed PubMed Central

6 Yang D, Xu D, Wang T, Yuan Z, Liu L, Shen Y, et al. Mitoquinone ameliorates cigarette smoke-induced airway inflammation and mucus hypersecretion in mice. Int Immunopharmacol 2021;90:107149.10.1016/j.intimp.2020.107149Search in Google Scholar PubMed

7 Chen R, Liang Y, Ip MSM, Zhang KY, Mak JCW. Amelioration of Cigarette Smoke-Induced Mucus Hypersecretion and Viscosity by Polysaccharides In Vitro and In Vivo. Oxid Med Cell Longev 2020;2020:8217642.10.1155/2020/8217642Search in Google Scholar PubMed PubMed Central

8 Val S, Belade E, George I, Boczkowski J, Baeza-Squiban A. Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin. Arch Toxicol 2012;86:1851–9.10.1007/s00204-012-0903-6Search in Google Scholar PubMed

9 He X, Zhang L, Xiong A, Ran Q, Wang J, Wu D, et al. PM2.5 aggravates NQO1-induced mucus hyper-secretion through release of neutrophil extracellular traps in an asthma model. Ecotoxicol Environ Saf 2021;218:112272.10.1016/j.ecoenv.2021.112272Search in Google Scholar PubMed

10 Gehrig S, Duerr J, Weitnauer M, Wagner CJ, Graeber SY, Schatterny J, et al. Lack of neutrophil elastase reduces inflammation, mucus hypersecretion, and emphysema, but not mucus obstruction, in mice with cystic fibrosis-like lung disease. Am J Respir Crit Care Med 2014;189:1082–92.10.1164/rccm.201311-1932OCSearch in Google Scholar PubMed

11 Siddiqui S, Johansson K, Joo A, Bonser LR, Koh KD, Le Tonqueze O, et al. Epithelial miR- 141 regulates IL-13-induced airway mucus production. JCI Insight 2021;6:139019.10.1172/jci.insight.139019Search in Google Scholar PubMed PubMed Central

12 Faiz A, Weckmann M, Tasena H, Vermeulen CJ, Van den Berge M, Ten Hacken NHT, et al. Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion. Eur Respir J 2018;52:1800310.10.1183/13993003.00310-2018Search in Google Scholar PubMed

13 Hammad H, Lambrecht BN. The basic immunology of asthma. Cell 2021;184:1469–85.10.1016/j.cell.2021.02.016Search in Google Scholar PubMed

14 Wang J. Casticin alleviates lipopolysaccharide-induced inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells through Nrf2/Keap1 and NF-κB pathways. Phytother Res: PTR 2018;32:1346–53.10.1002/ptr.6067Search in Google Scholar PubMed

15 Deshmukh HS, Case LM, Wesselkamper SC, Borchers MT, Martin LD, Shertzer HG, et al. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am J Respir Crit Care Med 2005;171:305–14.10.1164/rccm.200408-1003OCSearch in Google Scholar PubMed

16 Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest 1990;85:682–9.10.1172/JCI114492Search in Google Scholar PubMed PubMed Central

17 Kim S, Nadel JA. Role of neutrophils in mucus hypersecretion in COPD and implications for therapy. Treat Respir Med 2004;3:147–59.10.2165/00151829-200403030-00003Search in Google Scholar PubMed

18 Rubin BK, Priftis KN, Schmidt HJ, Henke MO. Secretory hyperresponsiveness and pulmonary mucus hypersecretion. Chest 2014;146:496–507.10.1378/chest.13-2609Search in Google Scholar PubMed

19 Oh S-Y, Kim Y-H, Kang M-K, Lee E-J, Kim D-Y, Oh H, et al. Aesculetin Inhibits Airway Thickening and Mucus Overproduction Induced by Urban Particulate Matter through Blocking Inflammation and Oxidative Stress Involving TLR4 and EGFR. Antioxidants (Basel) 2021;10:494.10.3390/antiox10030494Search in Google Scholar PubMed PubMed Central

20 Lai H, Rogers DF. New pharmacotherapy for airway mucus hypersecretion in asthma and COPD: targeting intracellular signaling pathways. J Aerosol Med Pulm Drug Deliv 2010;23:219–31.10.1089/jamp.2009.0802Search in Google Scholar PubMed

21 Xu H, Sun Q, Lu L, Luo F, Zhou L, Liu J, et al. MicroRNA-218 acts by repressing TNFR1-mediated activation of NF-κB, which is involved in MUC5AC hyper-production and inflammation in smoking-induced bronchiolitis of COPD. Toxicol Lett 2017;280:171–80.10.1016/j.toxlet.2017.08.079Search in Google Scholar PubMed

22 Gaffey K, Reynolds S, Plumb J, Kaur M, Singh D. Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs. Eur Respir J 2013;42:28–41.10.1183/09031936.00170711Search in Google Scholar PubMed

23 Fang S, Crews AL, Chen W, Park J, Yin Q, Ren X-R, et al. MARCKS and HSP70 interactions regulate mucin secretion by human airway epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 2013;304:L511–L8.10.1152/ajplung.00337.2012Search in Google Scholar PubMed PubMed Central

24 Li Y, Martin LD, Spizz G, Adler KB. MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cells in vitro. J Biol Chem 2001;276:40982–90.10.1074/jbc.M105614200Search in Google Scholar PubMed

25 Lai Y, Fois G, Flores JR, Tuvim MJ, Zhou Q, Yang K, et al. Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides. Nature 2022;603:949–56.10.1038/s41586-022-04543-1Search in Google Scholar PubMed PubMed Central

26 Jones LC, Moussa L, Fulcher ML, Zhu Y, Hudson EJ, O’Neal WK, et al. VAMP8 is a vesicle SNARE that regulates mucin secretion in airway goblet cells. J Physiol 2012;590:545–62.10.1113/jphysiol.2011.222091Search in Google Scholar PubMed PubMed Central

27 Åstrand ABM, Hemmerling M, Root J, Wingren C, Pesic J, Johansson E, et al. Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition. Am J Physiol Lung Cell Mol Physiol 2015;308:L22–L32.10.1152/ajplung.00163.2014Search in Google Scholar PubMed PubMed Central

28 Cloonan SM, Lam HC, Ryter SW, Choi AM. “Ciliophagy”: The consumption of cilia components by autophagy. Autophagy 2014;10:532–4.10.4161/auto.27641Search in Google Scholar PubMed PubMed Central

29 Li X, Jin F, Lee HJ, Lee CJ. Recent Advances in the Development of Novel Drug Candidates for Regulating the Secretion of Pulmonary Mucus. Biomol Ther (Seoul) 2020;28:293–301.10.4062/biomolther.2020.002Search in Google Scholar PubMed PubMed Central

30 Willemse BWM, ten Hacken NHT, Rutgers B, Lesman-Leegte IGAT, Timens W, Postma DS. Smoking cessation improves both direct and indirect airway hyperresponsiveness in COPD. Eur Respir J 2004;24:391–6.10.1183/09031936.04.00117603Search in Google Scholar PubMed

31 Takeyama K, Dabbagh K, Lee HM, Agustí C, Lausier JA, Ueki IF, et al. Epidermal growth factor system regulates mucin production in airways. Proc Natl Acad Sci U S A 1999;96:3081–6.10.1073/pnas.96.6.3081Search in Google Scholar PubMed PubMed Central

32 Ou X-M, Feng Y-L, Wen F-Q, Wang K, Yang J, Deng Z-P, et al. Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-kappaB. Respirology 2008;13:63–72.10.1111/j.1440-1843.2007.01213.xSearch in Google Scholar PubMed

33 Spagnolo P, Fabbri LM, Bush A. Long-term macrolide treatment for chronic respiratory disease. Eur Respir J 2013;42:239–51.10.1183/09031936.00136712Search in Google Scholar PubMed

34 Nogami H, Aizawa H, Matsumoto K, Nakano H, Koto H, Miyazaki H, et al. Neutrophil elastase inhibitor, ONO-5046 suppresses ozone-induced airway mucus hypersecretion in guinea pigs. Eur J Pharmacol 2000;390:197–202.10.1016/S0014-2999(99)00921-8Search in Google Scholar PubMed

35 Voynow JA, Young LR, Wang Y, Horger T, Rose MC, Fischer BM. Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. Am J Physiol 1999;276:L835–L43.10.1152/ajplung.1999.276.5.L835Search in Google Scholar PubMed

36 Atherton HC, Jones G, Danahay H. IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation. Am J Physiol Lung Cell Mol Physiol 2003;285:L730–L9.10.1152/ajplung.00089.2003Search in Google Scholar PubMed

37 Poole PJ, Black PN. Preventing exacerbations of chronic bronchitis and COPD: therapeutic potential of mucolytic agents. Am J Respir Med 2003;2:367–70.10.1007/BF03256664Search in Google Scholar PubMed

38 Rogers DF, Barnes PJ. Treatment of airway mucus hypersecretion. Ann Med 2006;38:116–25.10.1080/07853890600585795Search in Google Scholar PubMed

39 Ohar JA, Donohue JF, Spangenthal S. The Role of Guaifenesin in the Management of Chronic Mucus Hypersecretion Associated with Stable Chronic Bronchitis: A Comprehensive Review. Chronic Obstr Pulm Dis 2019;6:341–349..10.15326/jcopdf.6.4.2019.0139Search in Google Scholar PubMed PubMed Central

40 Lin VY, Kaza N, Birket SE, Kim H, Edwards LJ, LaFontaine J, et al. Excess mucus viscosity and airway dehydration impact COPD airway clearance. Eur Respir J 2020;55:1900419.10.1183/13993003.00419-2019Search in Google Scholar PubMed PubMed Central

41 Kellerman DJ. P2Y(2) receptor agonists: a new class of medication targeted at improved mucociliary clearance. Chest 2002;121:201S–5S.10.1378/chest.121.5_suppl.201SSearch in Google Scholar PubMed

42 McCormack P, Burnham P, Southern KW. Autogenic drainage for airway clearance in cystic fibrosis. Cochrane Database Syst Rev 2017;10:CD009595.10.1002/14651858.CD009595.pub2Search in Google Scholar PubMed PubMed Central

43 Osman LP, Roughton M, Hodson ME, Pryor JA. Short-term comparative study of high frequency chest wall oscillation and European airway clearance techniques in patients with cystic fibrosis. Thorax 2010;65:196–200.10.1136/thx.2008.111492Search in Google Scholar PubMed PubMed Central

44 Mineshita M, Inoue T, Miyazawa T. [Bronchoscopic treatments for COPD]. Nihon Rinsho 2016;74:807–12.Search in Google Scholar
Published Online: 2023-12-20

© 2023 Ruonan Yang, Xiaojie Wu, Abdelilah Soussi Gounni, Jungang Xie, published by De Gruyter on behalf of Scholar Media Publishing

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.2478/jtim-2023-0094
Creative Commons
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Articles in the same Issue

  1. Perspective
  2. Mucus hypersecretion in chronic obstructive pulmonary disease: From molecular mechanisms to treatment
  3. Timing of TIPS for the management of portal vein thrombosis in liver cirrhosis
  4. Commentary
  5. Could unpublishing negative results be harmful to the general public?
  6. Review Article
  7. Oncogenic KRAS triggers metabolic reprogramming in pancreatic ductal adenocarcinoma
  8. Mitochondrial damage-associated molecular patterns in chronic obstructive pulmonary disease: Pathogenetic mechanism and therapeutic target
  9. Exosomes and their derivatives as biomarkers and therapeutic delivery agents for cardiovascular diseases: Situations and challenges
  10. Autophagy-dependent ferroptosis in infectious disease
  11. Impact of gut microbiota and associated mechanisms on postprandial glucose levels in patients with diabetes
  12. Circular RNA: A promising new star of vaccine
  13. Crosstalk between gut microbiota and gut resident macrophages in inflammatory bowel disease
  14. Original Article
  15. Hypervolemia suppresses dilutional anaemic injury in a rat model of haemodilution
  16. Prognostic value of serum ammonia in critical patients with non-hepatic disease: A prospective, observational, multicenter study
  17. Global lineage evolution pattern of sars-cov-2 in Africa, America, Europe, and Asia: A comparative analysis of variant clusters and their relevance across continents
  18. Efficacy and safety of QL0911 in adult patients with chronic primary immune thrombocytopenia: A multicenter, randomized, double-blind, placebo-controlled, phase III trial
  19. A pan-cancer analysis of the oncogenic role of Golgi transport 1B in human tumors
  20. Short-term duration of diabetic retinopathy as a predictor for development of diabetic kidney disease
  21. Cardiac magnetic resonance imaging-derived septum swing index detects pulmonary hypertension: A diagnostic study
  22. Letter to Editor
  23. Temporal trend of acute myocardial infarction-related mortality and associated racial/ethnic disparities during the omicron outbreak
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