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  • Editorial
  • Open Access

The underestimated danger of E-cigarettes - also in the absence of nicotine

Respiratory Research201819:159

https://doi.org/10.1186/s12931-018-0870-4

  • Received: 3 May 2018
  • Accepted: 20 August 2018
  • Published:

Electronic cigarettes (E-cigarettes, ECs) are electronic devices that heat a liquid – usually comprising propylene glycol and glycerol, with or without nicotine and flavors, stored in disposable or refillable cartridges or a reservoir – into an aerosol (vapor) for inhalation [1]. Since ECs appeared on the market in 2006 they have become increasingly popular, especially among young people [1, 2]. E-cigarettes are marketed as a safer and “healthier” alternative to traditional cigarettes, and it is suggested in the mass media that ECs help smokers to stop smoking long-term, or to help smokers unable to stop smoking entirely to reduce their tobacco cigarette consumption [3]. However, the number of never-smoking youth who use ECs with or without nicotine is dramatically increasing. ECs are new sources of the highly addictive substance nicotine, which has a proven harmful effect on health [4, 5]. And, the advertising of nicotine-free ECs with liquids of fruit and sweet flavors is particularly likely to encourage young people to start using the E-cigarette. The Forum of International Respiratory Societies also revealed that E-cigarette (EC)-smoking is a significant public health problem because EC-use simulate smoking behaviour and can be done in public places, which together with its alarmingly growing popularity may increase the social approval for smoking and nicotine addiction [6].

In addition to the possible harmful effects of nicotine per se, the other main health concerns about EC-usage is the potential for toxic aldehyde emissions, such as formaldehyde, acetaldehyde, propanal and acrolein, which are known to be formed following heating of the EC-liquid main components propylene glycol and glycerol, as thermal decomposition products [7, 8]. Other contaminants inhaled by an EC-smoker during a “vaporization” session can be o-methyl-benzaldehyde, carcinogenic nitrosamines, terpenic compounds such as limonene (which are probably used by the manufacturers as flavoring agents) [911], as well as heavy metal and silicate particles (> 1 μm) including nanoparticles (< 100 nm) [12]. Interestingly, it has also been reported that the emission levels of aldehydes released by EC aerosols with and without flavorings, are generally very low [13, 14], and that high levels of formaldehyde emissions due to excessive degradation of propylene glycol can only be caused by unrealistic use conditions of ECs, such as overheating (remaining) faint levels of EC-liquids in the cartridges at a high voltage (5 V), which creates the unpleasant taste of “dry puffs” to EC-smokers and is thus normally avoided by users [13, 15, 16].

However, there is growing evidence from current studies suggesting that EC-smoking induces a signature of harm in the lung, which clearly challenges the concept that switching from traditional cigarettes to ECs is a healthier alternative. EC-smoke/EC-aerosol exposure has been demonstrated to induce oxidative stress, glutathione depletion and increased production of inflammatory cytokines in human airway epithelial cells in vitro and in lungs of mice in vivo [17]. Further, mice exposed to EC-smoke reveal impaired pulmonary anti-bacterial and anti-viral defenses in response to infection with S. pneumoniae and Influenza A virus, respectively [18]. These changes may play a role in the development of chronic airway diseases, such as chronic obstructive lung disease (COPD). In addition, DNA damage and impaired DNA repair mechanisms have recently been reported in human bronchial epithelial cells and in the mouse lung in response to EC-smoke exposure, suggesting enhanced susceptibility of the lung epithelium to oncogenic transformation and tumorigenesis [19]. In vivo evidence that EC-smoking/EC-aerosols can be harmful to the human lung stems from a recent study by Reidel et al. who compared 15 sputum samples from EC-users, 14 from current tobacco cigarette smokers and 15 from never-smokers by quantitative proteomics [20]. The underlying signature obtained from the sputum of EC-smokers is that of a unique innate immune response in the lung, involving increased neutrophilic activation and altered mucin secretion, as compared to never-smokers, and was in part overlapping with, but also distinct from that of healthy tobacco cigarette smokers to some extent. Additionally, signatures of increased reactive oxygen species (ROS) generation involving upregulation of aldehyde detoxification mechanisms were evident in both the EC-smokers and traditional cigarette smokers. However, the authors made it clear that most of the EC-smokers (12 of 15) were formerly tobacco cigarette smokers, thus questioning whether these results were solely related to EC-aerosols [20]. Therefore, studies designed to research EC-smokers without “former traditional cigarette-history” seem to be needed.

In their research article entitled “Altered lung biology of healthy never smokers following acute inhalation of E-cigarettes” in Volume 19 of the Respiratory Research-journal (Staudt et al.: Respir Res 2018, 19:78; [21]), Staudt and coworkers have researched the transcriptome in small airway epithelium (SAE) cells as well as in alveolar macrophages (AM) of healthy never-smoker indivduals with no history of exposure to any tobacco products or ECs (n = 10), versus SAE and AM obtained from the very same individuals after exposuring them to short-time EC-smoking in the absence (n = 3) or presence of nicotine (n = 7) in EC-aerosols. Short-time EC-smoking was defined by two exposures to 10 puffs with an interval of 30 min between both EC-usages. In their study, Staudt et al. could clearly demonstrate that short-time smoking of ECs is actually harmful to the lung, even in the absence of nicotine. They observed that the gene expression profiles were significantly altered in all conditions thereby indicating signatures of increased inflammation, impaired host-defense responses, p53-activation as well as pro-tumorigenic signaling relevant to lung cancer, as compared to the “never-smoking-state” before. In detail, the list of differentially regulated genes in supplemental Table IV of this paper [21] shows that SAE of individuals inhaling EC-smoke with nicotine indicated enhanced expression of the p53-activating tumor-suppressors AJUBA (Ajuba LIM protein) and LATS2 (large tumor suppressor kinase-2) on the one side [22, 23], but simultaneously significant upregulation of well-known tumor and metastasis promoting factors, such as SERPINB2 (=PAI2, plasminogen activator inhibitor-2) and EDN1 (endothelin-1) on the other side [24, 25]. Notably, EC-smoking without nicotine (supplemental Table V in [21]) also resulted in significant activation of genes with a prominent role in promoting tumorigenesis, such as BATF3 (basic leucine zipper transcription factor, ATF-like 3) [26], S100P (S100 calcium binding protein P) [27], CEACAM5 (carcinoembryonic antigen-related cell adehesion molecule-5), and FGFBP1 (fibroblast growth factor binding protein-1) [28]. FGFBP1 enhances FGF signaling including angiogenesis during cancer progression and is upregulated in various cancers [28], and S100P has been identified as target gene of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway in lung cancer cells, which is observed to be hyperactivated in most non-small cell lung cancers (NSCLCs) [27]. In line with this pro-tumorigenic signature, down-regulated genes included the circadian clock component PER3 (period circadian clock 3), and loss of PER3 has been suggested as a novel prognostic biomarker in patients with NSCLC [29]. Further, EC-smoking in the absence of nicotine led to upregulation of LTB4R2 (leukotriene B4 receptor-2) and ISG20 (interferon stimulated exonuclease gene-20 kDa) in SAE cells, which are indicative of increased inflammation and activated host innate immune signaling [30, 31]. Induction of expression and pro-inflammatory functions of LTB4R2 receptor have been demonstrated in bronchial epithelial cells in response to cigarette smoke extracts (CSE)-exposure in vitro, which promoted the adhesiveness of neutrophils to bronchial cells, a mechanism that has been suggested to contribute to airway neutrophilia and tissue damage in COPD in vivo [30]. Moreover, upregulation of the transcription factor SPDEF (SAM pointed domain-containing Ets transcription factor), a key positive regulator of the airway secretory mucin MUC5AC [32], suggests an elevated mucin concentration in SAE in response to EC-aerosol inhaling, and which indeed was observed in the study by Reidel B et al. in the sputum of EC-smokers [20]. It has been suggested that an elevated mucin concentration is an important hallmark of failed mucus transport in mucoobstructive disease and an important parameter in COPD pathogenesis [20, 33].

The AM transcriptome data of individuals inhaling EC-aerosols with nicotine (supplemental Table VI in [21]) indicated differentially regulated genes involved in host-pathogen interactions and immune-response, involving upregulated ICAM4 (intercellular adhesion molecule 4) expression [34] and downregulation of CCL28 chemokine, which has been reported to possess potent antimicrobial activity [35]. ICAM-4 has been reported to support host cell invasion by M. tuberculosis through direct binding of this pathogen [34], and its upregulation in response to nicotine-containing EC-smoke could indicate an increased susceptibility to bacterial invasion of macrophages in EC-users. Similar to the SAE transcriptome data, AM of EC-smokers inhaling nicotine-free aerosols (supplemental Table VII in [21]) also indicated a protumorigenic signature, as shown by increased expression of PTGER3 [prostaglandin E2 (PGE2) receptor EP3 subtype] and CCNB2 (cyclin B2) [36, 37]. Upregulated expression of CCNB2 mRNA in tumor cells has been demonstrated to correlate with a poor prognosis in patients with NSCLC [37]. PGE2/EP3-receptor signaling has been reported to promote tumor growth in NSCLC through nuclear translocation of epidermal growth factor receptor (EGFR) and consequent up-regulation of cyclin D1 and c-Myc [36]. Increased PGE2/EP3-receptor signaling has also been observed to suppress lung innate immunity against S. pneumoniae [38], whereas Ptger3 deletion improves pulmonary host defense and protects mice from death in severe S. pneumoniae infections or lipopolysaccharide (LPS) exposure [39]. Importantly, the signature of an increased susceptibility to respiratory bacterial infections was also supported by decreased expression of the immune response gene ITGA6 (integrin alpha-6) [40] and the transcription factor FOXM1 (Forkhead box protein M1), a critical mediator of lung development. It has been shown that Foxm1 regulates resolution of hyperoxic lung injury in neonatal mice, through inhibiting neutrophil-derived enzymes and enhancing monocytic responses that limit alveolar epithelial injury [41].

Taken together, these results by Staudt et al. unequivocally indicate that even short-time EC-smoking dysregulates biology of the human lung in vivo, independently of nicotine, and that inhaling of the non-nicotine derived chemicals present in EC-aerosols are actually harmful to SAE cells and AMs in EC-smokers, despite the limited and “correct” use of EC-devices (with avoiding “dry puffs”). As outlined, the observed gene expression changes in response to EC-aerosol exposure may have significant implications for lung tissue injury responses. Moreover, the transcriptome data are very well presented and will be a reference for other scientists looking at affected genes for studying the potential adverse effects of ECs. Though, it should be considered, that only one brand, namely “Blu EC” with and without nicotine, was analyzed in the study by Staudt and coworkers [21]. But the types or concentrations of chemicals a person is exposed to is varying by brand and type of device; and no-one can yet really estimate the harms of chemical reaction products formed in EC-aerosols from the plenty of merchandised EC-liquids with various flavoring compounds, which are thousands today and which differ by brand and manufacturer.

Conclusion

In conclusion, the results of the study by Staudt et al. expand our insights about adverse effects of ECs, and at the very least, suggest that quoting ECs being considerably less harmful to health as compared to traditional cigarettes should be avoided until complete data on the safety and health impact of EC-smoking and various EC-aerosols are available. Due to lack of these informations, the Forum of International Respiratory Societies advances the view, that ECs should be restricted or banned, which is reasonable [6].

Abbreviations

AJUBA

Ajuba LIM protein

AM: 

Alveolar macrophages

BATF3

Basic leucine zipper transcription factor, ATF-like 3

CCL28

C-C motif chemokine 28

CCNB2

Cyclin B2

CEACAM5

Carcinoembryonic antigen-related cell adhesion molecule-5

COPD: 

Chronic obstructive lung disease

CSE: 

Cigarette smoke extracts

EC(s): 

E-cigarette(s), electronic cigarette(s)

EDN1

Endothelin-1

EGFR: 

Epidermal growth factor receptor

FGFBP1

Fibroblast growth factor binding protein-1

FOXM1

Forkhead box protein M1

ICAM4

Intercellular adhesion molecule 4

ISG20

Interferon stimulated exonuclease gene-20 kDa

ITGA6

Integrin alpha-6

LATS2

Large tumor suppressor kinase-2

LPS: 

Lipopolysaccharide

LTB4R2

Leukotriene B4 receptor-2

M. tuberculosis

Mycobacterium tuberculosis

MUC5AC

Mucin-5 AC

NSCLC: 

Non-small cell lung cancers

PER3

Period circadian clock 3

PI3K/Akt: 

Phosphoinositide 3-kinase/protein kinase B

PTGER3

Prostaglandin E2 (PGE2) receptor EP3 subtype

ROS: 

Reactive oxygen species

S. pneumoniae

Streptococcus pneumoniae

S100P

S100 calcium binding protein P

SAE: 

Small airway epithelium

SERPINB2 = PAI2

Plasminogen activator inhibitor-2

SPDEF

SAM pointed domain-containing Ets transcription factor

Declarations

Author’s contribution

MK studied literature, performed data interpretation and wrote the editorial. The author read and approved the final manuscript.

Ethics approval and consent to participate

I wrote an editorial about the research article from Staudt and coworkers, including a description of their transcriptomic data of small airway epithelium (SAE) cells and alveolar macrophages (AM) obtained from human individuals. In their article, Staudt et al. included statements on ethics approval and consent, and stated the committees that approved the studies. According to the German Guidelines for Secondary Data Analysis, inclusion of statements on ethical approval and consent to participate is not required for this editorial.

Consent for publication

Not applicable.

Competing interests

M. Korfei declares that she has no competing interests regarding this specific article.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Internal Medicine II, Klinikstrasse 36, 35392 Giessen, Germany
(2)
Biomedical Research Center Seltersberg (BFS), Justus-Liebig-University Giessen, Schubertstrasse 81, 35392 Giessen, Germany
(3)
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany

References

  1. Caponnetto P, Campagna D, Papale G, Russo C, Polosa R. The emerging phenomenon of electronic cigarettes. Expert Rev Respir Med. 2012;6:63–74.View ArticlePubMedGoogle Scholar
  2. Murthy VH. E-cigarette use among youth and young adults: a major public health concern. JAMA Pediatr. 2017;171:209–10.View ArticlePubMedGoogle Scholar
  3. Grana RA, Popova L, Ling PM. A longitudinal analysis of electronic cigarette use and smoking cessation. JAMA Intern Med. 2014;174:812–3.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology. 2010;210:453–69.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362:2295–303.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Schraufnagel DE, Blasi F, Drummond MB, Lam DC, Latif E, Rosen MJ, Sansores R, Van Zyl-Smit R. Electronic cigarettes. A position statement of the forum of international respiratory societies. Am J Respir Crit Care Med. 2014;190:611–8.View ArticlePubMedGoogle Scholar
  7. Uchiyama S, Ohta K, Inaba Y, Kunugita N. Determination of carbonyl compounds generated from the E-cigarette using coupled silica cartridges impregnated with hydroquinone and 2,4-dinitrophenylhydrazine, followed by high-performance liquid chromatography. Anal Sci. 2013;29:1219–22.View ArticlePubMedGoogle Scholar
  8. Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hidden formaldehyde in e-cigarette aerosols. N Engl J Med. 2015;372:392–4.View ArticlePubMedGoogle Scholar
  9. Goniewicz ML, Knysak J, Gawron M, Kosmider L, Sobczak A, Kurek J, Prokopowicz A, Jablonska-Czapla M, Rosik-Dulewska C, Havel C, et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control. 2014;23:133–9.View ArticlePubMedGoogle Scholar
  10. McAuley TR, Hopke PK, Zhao J, Babaian S. Comparison of the effects of e-cigarette vapor and cigarette smoke on indoor air quality. Inhal Toxicol. 2012;24:850–7.View ArticlePubMedGoogle Scholar
  11. Varlet V, Farsalinos K, Augsburger M, Thomas A, Etter JF. Toxicity assessment of refill liquids for electronic cigarettes. Int J Environ Res Public Health. 2015;12:4796–815.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Williams M, Villarreal A, Bozhilov K, Lin S, Talbot P. Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosol. PLoS One. 2013;8:e57987.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Farsalinos KE, Kistler KA, Pennington A, Spyrou A, Kouretas D, Gillman G. Aldehyde levels in e-cigarette aerosol: findings from a replication study and from use of a new-generation device. Food Chem Toxicol. 2018;111:64–70.View ArticlePubMedGoogle Scholar
  14. Farsalinos KE, Voudris V. Do flavouring compounds contribute to aldehyde emissions in e-cigarettes? Food Chem Toxicol. 2018;115:212–7.View ArticlePubMedGoogle Scholar
  15. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015;110:1352–6.View ArticlePubMedGoogle Scholar
  16. Farsalinos KE, Voudris V, Spyrou A, Poulas K. E-cigarettes emit very high formaldehyde levels only in conditions that are aversive to users: a replication study under verified realistic use conditions. Food Chem Toxicol. 2017;109:90–4.View ArticlePubMedGoogle Scholar
  17. Lerner CA, Sundar IK, Yao H, Gerloff J, Ossip DJ, McIntosh S, Robinson R, Rahman I. Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung. PLoS One. 2015;10:e0116732.View ArticlePubMedPubMed CentralGoogle Scholar
  18. Sussan TE, Gajghate S, Thimmulappa RK, Ma J, Kim JH, Sudini K, Consolini N, Cormier SA, Lomnicki S, Hasan F, et al. Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One. 2015;10:e0116861.View ArticlePubMedPubMed CentralGoogle Scholar
  19. Lee HW, Park SH, Weng MW, Wang HT, Huang WC, Lepor H, Wu XR, Chen LC, Tang MS. E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells. Proc Natl Acad Sci U S A. 2018;115:E1560–9.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Reidel B, Radicioni G, Clapp PW, Ford AA, Abdelwahab S, Rebuli ME, Haridass P, Alexis NE, Jaspers I, Kesimer M. E-cigarette use causes a unique innate immune response in the lung, involving increased neutrophilic activation and altered mucin secretion. Am J Respir Crit Care Med. 2018;197:492–501.View ArticlePubMedGoogle Scholar
  21. Staudt MR, Salit J, Kaner RJ, Hollmann C, Crystal RG. Altered lung biology of healthy never smokers following acute inhalation of E-cigarettes. Respir Res. 2018;19:78.View ArticlePubMedPubMed CentralGoogle Scholar
  22. Tanaka I, Osada H, Fujii M, Fukatsu A, Hida T, Horio Y, Kondo Y, Sato A, Hasegawa Y, Tsujimura T, Sekido Y. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade. Oncogene. 2015;34:73–83.View ArticlePubMedGoogle Scholar
  23. Visser S, Yang X. LATS tumor suppressor: a new governor of cellular homeostasis. Cell Cycle. 2010;9:3892–903.View ArticlePubMedGoogle Scholar
  24. Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH, Lee DJ, Chaft JE, Kris MG, Huse JT, Brogi E, Massague J. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014;156:1002–16.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Moody TW, Ramos-Alvarez I, Moreno P, Mantey SA, Ridnour L, Wink D, Jensen RT. Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells. Peptides. 2017;90:90–9.View ArticlePubMedPubMed CentralGoogle Scholar
  26. Schleussner N, Merkel O, Costanza M, Liang HC, Hummel F, Romagnani C, Durek P, Anagnostopoulos I, Hummel M, Johrens K, et al. The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma. Leukemia. 2018;Google Scholar
  27. De Marco C, Laudanna C, Rinaldo N, Oliveira DM, Ravo M, Weisz A, Ceccarelli M, Caira E, Rizzuto A, Zoppoli P, et al. Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer. PLoS One. 2017;12:e0178865.View ArticlePubMedPubMed CentralGoogle Scholar
  28. Schmidt MO, Garman KA, Lee YG, Zuo C, Beck PJ, Tan M, Aguilar-Pimentel JA, Ollert M, Schmidt-Weber C, Fuchs H, et al. The role of fibroblast growth factor-binding protein 1 in skin carcinogenesis and inflammation. J Invest Dermatol. 2018;138:179–88.View ArticlePubMedGoogle Scholar
  29. Liu B, Xu K, Jiang Y, Li X. Aberrant expression of Per1, Per2 and Per3 and their prognostic relevance in non-small cell lung cancer. Int J Clin Exp Pathol. 2014;7:7863–71.PubMedPubMed CentralGoogle Scholar
  30. Pace E, Ferraro M, Di Vincenzo S, Bruno A, Giarratano A, Scafidi V, Lipari L, Di Benedetto DV, Sciarrino S, Gjomarkaj M. Cigarette smoke increases BLT2 receptor functions in bronchial epithelial cells: in vitro and ex vivo evidence. Immunology. 2013;139:245–55.View ArticlePubMedPubMed CentralGoogle Scholar
  31. Zeng X, Wang S, Chi X, Chen SL, Huang S, Lin Q, Xie B, Chen JL. Infection of goats with goatpox virus triggers host antiviral defense through activation of innate immune signaling. Res Vet Sci. 2016;104:40–9.View ArticlePubMedGoogle Scholar
  32. Chen G, Volmer AS, Wilkinson KJ, Deng Y, Jones LC, Yu D, Bustamante-Marin XM, Burns KA, Grubb BR, O'Neal WK, et al. Role of Spdef in the regulation of Muc5b expression in the Airways of Naive and Muco-obstructed Mice. Am J Respir Cell Mol Biol. 2018;Google Scholar
  33. Kesimer M, Ford AA, Ceppe A, Radicioni G, Cao R, Davis CW, Doerschuk CM, Alexis NE, Anderson WH, Henderson AG, et al. Airway mucin concentration as a marker of chronic bronchitis. N Engl J Med. 2017;377:911–22.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Bhalla K, Chugh M, Mehrotra S, Rathore S, Tousif S, Prakash Dwivedi V, Prakash P, Kumar Samuchiwal S, Kumar S, Kumar Singh D, et al. Host ICAMs play a role in cell invasion by Mycobacterium tuberculosis and plasmodium falciparum. Nat Commun. 2015;6:6049.View ArticlePubMedGoogle Scholar
  35. Matsuo K, Nagakubo D, Yamamoto S, Shigeta A, Tomida S, Fujita M, Hirata T, Tsunoda I, Nakayama T, Yoshie O. CCL28-deficient mice have reduced IgA antibody-secreting cells and an altered microbiota in the colon. J Immunol. 2018;200:800–9.View ArticlePubMedGoogle Scholar
  36. Bazzani L, Donnini S, Finetti F, Christofori G, Ziche M. PGE2/EP3/SRC signaling induces EGFR nuclear translocation and growth through EGFR ligands release in lung adenocarcinoma cells. Oncotarget. 2017;8:31270–87.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Takashima S, Saito H, Takahashi N, Imai K, Kudo S, Atari M, Saito Y, Motoyama S, Minamiya Y. Strong expression of cyclin B2 mRNA correlates with a poor prognosis in patients with non-small cell lung cancer. Tumour Biol. 2014;35:4257–65.View ArticlePubMedGoogle Scholar
  38. Lebender LF, Prunte L, Rumzhum NN, Ammit AJ. Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: implications for lung health and disease. Pulm Pharmacol Ther. 2018;49:75–87.View ArticlePubMedGoogle Scholar
  39. Aronoff DM, Lewis C, Serezani CH, Eaton KA, Goel D, Phipps JC, Peters-Golden M, Mancuso P. E-prostanoid 3 receptor deletion improves pulmonary host defense and protects mice from death in severe Streptococcus pneumoniae infection. J Immunol. 2009;183:2642–9.View ArticlePubMedPubMed CentralGoogle Scholar
  40. Pinto AR, Godwin JW, Chandran A, Hersey L, Ilinykh A, Debuque R, Wang L, Rosenthal NA. Age-related changes in tissue macrophages precede cardiac functional impairment. Aging (Albany NY). 2014;6:399–413.View ArticleGoogle Scholar
  41. Xia H, Ren X, Bolte CS, Ustiyan V, Zhang Y, Shah TA, Kalin TV, Whitsett JA, Kalinichenko VV. Foxm1 regulates resolution of hyperoxic lung injury in newborns. Am J Respir Cell Mol Biol. 2015;52:611–21.View ArticlePubMedPubMed CentralGoogle Scholar

Copyright

© The Author(s). 2018

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