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Pulmonary Inflammation and KRAS Mutation in Lung Cancer

Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1303)

Abstract

Chronic lung infection and lung cancer are two of the most important pulmonary diseases. Respiratory infection and its associated inflammation have been increasingly investigated for their role in increasing the risk of respiratory diseases including chronic obstructive pulmonary disease (COPD) and lung cancer. Kirsten rat sarcoma viral oncogene (KRAS) is one of the most important regulators of cell proliferation, differentiation, and survival. KRAS mutations are among the most common drivers of cancer. Lung cancer harboring KRAS mutations accounted for ~25% of the incidence but the relationship between KRAS mutation and inflammation remains unclear. In this chapter, we will describe the roles of KRAS mutation in lung cancer and how elevated inflammatory responses may increase KRAS mutation rate and create a vicious cycle of chronic inflammation and KRAS mutation that likely results in persistent potentiation for KRAS-associated lung tumorigenesis. We will discuss in this chapter regarding the studies of KRAS gene mutations in specimens from lung cancer patients and in animal models for investigating the role of inflammation in increasing the risk of lung tumorigenesis driven primarily by oncogenic KRAS.

Keywords

Inflammation KRAS mutation Tumor microenvironment COPD Lung cancer 

Abbreviations

AKT

protein kinase B

ALK

anaplastic lymphoma receptor tyrosine kinase genes

BALF

bronchoalveolar lavage fluid

BHT

butylated hydroxytoluene

CCSP

club cell secretory protein, aka CC10

COPD

chronic obstructive pulmonary disease

COX

cyclooxygenase

CXCL5

C-X-C motif chemokine 5

EGFR

epidermal growth factor receptor

ERK

extracellular signal-regulated kinase

FOXP3

forkhead box P3

G-CSF

granulocyte colony-stimulating factor

GDP

guanosine diphosphate

GM-CSF

granulocyte-macrophage colony-stimulating factor

GTP

guanosine triphosphate

HIF-1α

Hypoxia-inducible factor 1-alpha, aka HIF-1-alpha

ICB

immune checkpoint blockade

IDO1

indoleamine 2,3-dioxygenase

IFN

interferon-γ

IL

Interleukin

KC

keratinocyte chemoattractant

KRAS

Kirsten rat sarcoma viral oncogene

LAG3

lymphocyte-activation gene 3

MAPK

mitogen-activated protein kinase

MCA

3-methylcholanthrene, aka 3-MC

MCP-1

monocyte chemotactic protein 1

MDSC

myeloid-derived suppressor cell

MHC

major histocompatibility complex

MIP-1α

macrophage inflammatory protein 1 alpha

MIP-2

macrophage inflammatory protein 2

mTOR

mammalian target of rapamycin

NDMA

N-nitrosodimethylamine

NNK

nitrosamine 4-(methylnitrosamino)-1-(3- pyridyl)-l-butanone

NSCLC

non-small cell lung cancer

NTHi

nontypeable Haemophilus influenzae

PAH

polycyclic aromatic hydrocarbons

PD-1

programmed cell death protein 1

PI3K

phosphatidylinositol-3 kinase

PTEN

phosphatase and tensin homologue deleted from chromosome 10

ROS

reactive oxygen species

SCLC

small cell lung carcinoma

TGF-β

transforming growth factor beta

TNF

tumor necrosis factor

TNM

tumor (T), node (N), metastasis (M)

Treg

regulatory T cell

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Notes

Acknowledgments

This research is supported by NIH awards HL125128 and AI133351 (to YPD).

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Torre LA, Siegel RL, Jemal A. Lung Cancer statistics. Adv Exp Med Biol. 2016;893:1–19.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD. Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e1S–e29S.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol. 2007;25:561–70.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J. 1976;2:1525–36.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst. 1993;85:457–64.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res. 2018;7:220–33.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–94.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Soh J, Toyooka S, Okumura N, Nakamura H, Nakata M, Yamashita M, Sakamoto J, Aoe M, Hotta K, Morita S, Date H. Impact of pathological stage and histological subtype on clinical outcome of adjuvant chemotherapy of paclitaxel plus carboplatin versus oral uracil-tegafur for non-small cell lung cancer: subanalysis of SLCG0401 trial. Int J Clin Oncol. 2019;24:1367–76.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Straif K, Benbrahim-Tallaa L, Baan R, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Guha N, Freeman C, Galichet L, Cogliano V, Group, W. H. O. I. A. f. R. o. C. M. W. A review of human carcinogens–Part C: metals, arsenic, dusts, and fibres. Lancet Oncol. 2009;10:453–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Driscoll T, Nelson DI, Steenland K, Leigh J, Concha-Barrientos M, Fingerhut M, Pruss-Ustun A. The global burden of disease due to occupational carcinogens. Am J Ind Med. 2005;48:419–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Humans, I. W. G. o. t. E. o. C. R. t. Arsenic, metals, fibres, and dusts. IARC Monogr Eval Carcinog Risks Hum. 2012;100:11–465.Google Scholar
  13. 13.
    Conway EM, Pikor LA, Kung SH, Hamilton MJ, Lam S, Lam WL, Bennewith KL. Macrophages, inflammation, and lung cancer. Am J Respir Crit Care Med. 2016;193:116–30.PubMedCrossRefGoogle Scholar
  14. 14.
    Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, Ginsberg RJ. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg. 1995;109:120–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Harpole DH Jr, Herndon JE 2nd, Young WG Jr, Wolfe WG, Sabiston DC Jr. Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer. 1995;76:787–96.PubMedCrossRefGoogle Scholar
  16. 16.
    al-Kattan, K., Sepsas, E., Fountain, S. W., and Townsend, ER. (1997) Disease recurrence after resection for stage I lung cancer, Eur J Cardiothorac Surg 12, 380–384.CrossRefGoogle Scholar
  17. 17.
    Nakagawa T, Okumura N, Ohata K, Igai H, Matsuoka T, Kameyama K. Postrecurrence survival in patients with stage I non-small cell lung cancer. Eur J Cardiothorac Surg. 2008;34:499–504.PubMedCrossRefGoogle Scholar
  18. 18.
    Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L, International Association for the Study of Lung Cancer International Staging, C., and Participating, I. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:706–14.PubMedCrossRefGoogle Scholar
  19. 19.
    Bradbury P, Sivajohanathan D, Chan A, Kulkarni S, Ung Y, Ellis PM. Postoperative adjuvant systemic therapy in completely resected non-small-cell lung cancer: a systematic review. Clin Lung Cancer. 2017;18:259–273 e258.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, International Adjuvant Lung Cancer Trial Collaborative, G. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351–60.PubMedCrossRefGoogle Scholar
  21. 21.
    Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F, National Cancer Institute of Canada Clinical Trials, G., and National Cancer Institute of the United States Intergroup, J. B. R. T. I. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352:2589–97.PubMedCrossRefGoogle Scholar
  22. 22.
    Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzales-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine international Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006;7:719–27.PubMedCrossRefGoogle Scholar
  23. 23.
    Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F, Investigators P. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77.PubMedCrossRefGoogle Scholar
  24. 24.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.PubMedCrossRefGoogle Scholar
  25. 25.
    Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11:473–81.PubMedCrossRefGoogle Scholar
  27. 27.
    Lievense LA, Sterman DH, Cornelissen R, Aerts JG. Checkpoint blockade in lung cancer and mesothelioma. Am J Respir Crit Care Med. 2017;196:274–82.PubMedCrossRefGoogle Scholar
  28. 28.
    Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, Wurtz A, Dong W, Cai G, Melnick MA, Du VY, Schlessinger J, Goldberg SB, Chiang A, Sanmamed MF, Melero I, Agorreta J, Montuenga LM, Lifton R, Ferrone S, Kavathas P, Rimm DL, Kaech SM, Schalper K, Herbst RS, Politi K. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 2017;7:1420–35.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Homet Moreno B, Mezzadra R, Chmielowski B, Ruchalski K, Shintaku IP, Sanchez PJ, Puig-Saus C, Cherry G, Seja E, Kong X, Pang J, Berent-Maoz B, Comin-Anduix B, Graeber TG, Tumeh PC, Schumacher TN, Lo RS, Ribas A. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819–29.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210:1389–402.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Auerbach O, Stout AP, Hammond EC, Garfinkel L. Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med. 1961;265:253–67.PubMedCrossRefGoogle Scholar
  32. 32.
    Billatos E, Duan F, Moses E, Marques H, Mahon I, Dymond L, Apgar C, Aberle D, Washko G, Spira A, investigators, D. Detection of early lung cancer among military personnel (DECAMP) consortium: study protocols. BMC Pulm Med. 2019;19:59.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kaneda M, Yokoi K, Ito S, Niwa H, Takao M, Kondo R, Arimura T, Saito Y. The value of pleural lavage cytology examined during surgery for primary lung cancer. Eur J Cardiothorac Surg. 2012;41:1335–41.PubMedCrossRefGoogle Scholar
  34. 34.
    Saccomanno G, Archer VE, Auerbach O, Saunders RP, Brennan LM. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer. 1974;33:256–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Harris CC. Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res. 1991;51:5023s–44s.PubMedGoogle Scholar
  36. 36.
    Sozzi G, Miozzo M, Pastorino U, Pilotti S, Donghi R, Giarola M, De Gregorio L, Manenti G, Radice P, Minoletti F, et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 1995;55:135–40.PubMedGoogle Scholar
  37. 37.
    Stanley LA. Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. Toxicology. 1995;96:173–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Li Z, Xia J, Fang M, Xu Y. Epigenetic regulation of lung cancer cell proliferation and migration by the chromatin remodeling protein BRG1. Oncogenesis. 2019;8:66.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lok BH, Rudin CM. Epigenetic targeting of DNA repair in lung cancer. Proc Natl Acad Sci U S A. 2019;116:22429–31.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Bishop JM. Molecular themes in oncogenesis. Cell. 1991;64:235–48.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Enfield KSS, Marshall EA, Anderson C, Ng KW, Rahmati S, Xu Z, Fuller M, Milne K, Lu D, Shi R, Rowbotham DA, Becker-Santos DD, Johnson FD, English JC, MacAulay CE, Lam S, Lockwood WW, Chari R, Karsan A, Jurisica I, Lam WL. Epithelial tumor suppressor ELF3 is a lineage-specific amplified oncogene in lung adenocarcinoma. Nat Commun. 2019;10:5438.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Zarredar H, Pashapour S, Farajnia S, Ansarin K, Baradaran B, Ahmadzadeh V, Safari F. Targeting the KRAS, p38alpha, and NF-kappaB in lung adenocarcinoma cancer cells: the effect of combining RNA interferences with a chemical inhibitor. J Cell Biochem. 2019;120:10670–7.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci. 2005;118:843–6.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Prieto-Dominguez N, Parnell C, Teng Y. Drugging the small GTPase pathways in cancer treatment: promises and challenges. Cell. 2019;8:255.CrossRefGoogle Scholar
  45. 45.
    Milburn MV, Tong L, deVos AM, Brunger A, Yamaizumi Z, Nishimura S, Kim SH. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science. 1990;247:939–45.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Moll HP, Pranz K, Musteanu M, Grabner B, Hruschka N, Mohrherr J, Aigner P, Stiedl P, Brcic L, Laszlo V, Schramek D, Moriggl R, Eferl R, Moldvay J, Dezso K, Lopez-Casas PP, Stoiber D, Hidalgo M, Penninger J, Sibilia M, Gyorffy B, Barbacid M, Dome B, Popper H, Casanova E. Afatinib restrains K-RAS-driven lung tumorigenesis. Sci Transl Med. 2018;10(446):eaao2301. https://doi.org/10.1126/scitranslmed.aao2301.
  47. 47.
    Rezatabar S, Karimian A, Rameshknia V, Parsian H, Majidinia M, Kopi TA, Bishayee A, Sadeghinia A, Yousefi M, Monirialamdari M, Yousefi B. RAS/MAPK signaling functions in oxidative stress, DNA damage response and cancer progression. J Cell Physiol. 2019;  https://doi.org/10.1002/jcp.28334.
  48. 48.
    Sexton RE, Mpilla G, Kim S, Philip PA, Azmi AS. Ras and exosome signaling. Semin Cancer Biol. 2019;54:131–7.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Scheffzek K, Shivalingaiah G. Ras-specific GTPase-activating proteins-structures, mechanisms, and interactions. Cold Spring Harb Perspect Med. 2019;9(3):a031500.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Terrell EM, Morrison DK. Ras-mediated activation of the Raf family kinases. Cold Spring Harb Perspect Med. 2019;9:a033746.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Qu L, Pan C, He SM, Lang B, Gao GD, Wang XL, Wang Y. The Ras superfamily of small GTPases in non-neoplastic cerebral diseases. Front Mol Neurosci. 2019;12:121.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Zinatizadeh MR, Momeni SA, Zarandi PK, Chalbatani GM, Dana H, Mirzaei HR, Akbari ME, Miri SR. The role and function of Ras-association domain family in cancer: a review. Genes Dis. 2019;6:378–84.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Munoz-Maldonado C, Zimmer Y, Medova M. A comparative analysis of individual RAS mutations in Cancer biology. Front Oncol. 2019;9:1088.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Fernandez-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011;2:344–58.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lanfredini S, Thapa A, O’Neill E. RAS in pancreatic cancer. Biochem Soc Trans. 2019;47:961–72.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Hobbs GA, Wittinghofer A, Der CJ. Selective targeting of the KRAS G12C mutant: kicking KRAS when it’s down. Cancer Cell. 2016;29:251–3.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Li S, Balmain A, Counter CM. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer. 2018;18:767–77.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Prior IA, Hood FE, Hartley JL. The frequency of Ras mutations in cancer. Cancer Res. 2020;80:2969–74.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Gao W, Jin J, Yin J, Land S, Gaither-Davis A, Christie N, Luketich JD, Siegfried JM, Keohavong P. KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients. Mol Carcinog. 2017;56:381–8.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Siegfried JM, Gillespie AT, Mera R, Casey TJ, Keohavong P, Testa JR, Hunt JD. Prognostic value of specific KRAS mutations in lung adenocarcinomas. Cancer Epidemiol Biomark Prev. 1997;6:841–7.Google Scholar
  61. 61.
    Kitagawa Y, Okumura K, Watanabe T, Tsukamoto K, Kitano S, Nankinzan R, Suzuki T, Hara T, Soda H, Denda T, Yamaguchi T, Nagase H. Enrichment technique to allow early detection and monitor emergence of KRAS mutation in response to treatment. Sci Rep. 2019;9:11346.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Fu Y, Duan X, Huang J, Huang L, Zhang L, Cheng W, Ding S, Min X. Detection of KRAS mutation via ligation-initiated LAMP reaction. Sci Rep. 2019;9:5955.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Kadota K, Sima CS, Arcila ME, Hedvat C, Kris MG, Jones DR, Adusumilli PS, Travis WD. KRAS mutation is a significant prognostic factor in early-stage lung adenocarcinoma. Am J Surg Pathol. 2016;40:1579–90.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    El Osta B, Behera M, Kim S, Berry LD, Sica G, Pillai RN, Owonikoko TK, Kris MG, Johnson BE, Kwiatkowski DJ, Sholl LM, Aisner DL, Bunn PA, Khuri FR, Ramalingam SS. Characteristics and outcomes of patients with metastatic KRAS-mutant lung adenocarcinomas: the lung cancer mutation consortium experience. J Thorac Oncol. 2019;14:876–89.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:201–5.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    DeMarini DM, Landi S, Tian D, Hanley NM, Li X, Hu F, Roop BC, Mass MJ, Keohavong P, Gao W, Olivier M, Hainaut P, Mumford JL. Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions. Cancer Res. 2001;61:6679–81.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhu D, Keohavong P, Finkelstein SD, Swalsky P, Bakker A, Weissfeld J, Srivastava S, Whiteside TL. K-ras gene mutations in normal colorectal tissues from K-ras mutation-positive colorectal cancer patients. Cancer Res. 1997;57:2485–92.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Dong ZY, Zhong WZ, Zhang XC, Su J, Xie Z, Liu SY, Tu HY, Chen HJ, Sun YL, Zhou Q, Yang JJ, Yang XN, Lin JX, Yan HH, Zhai HR, Yan LX, Liao RQ, Wu SP, Wu YL. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2017;23:3012–24.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Smith LE, Denissenko MF, Bennett WP, Li H, Amin S, Tang M, Pfeifer GP. Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons. J Natl Cancer Inst. 2000;92:803–11.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Jimma Y, Jimma K, Yachi M, Hakata S, Habano W, Ozawa S, Terashima J. Aryl hydrocarbon receptor mediates cell proliferation enhanced by Benzo[a]pyrene in human lung cancer 3D spheroids. Cancer Investig. 2019;37:367–75.CrossRefGoogle Scholar
  71. 71.
    Keohavong P, Kahkonen B, Kinchington E, Yin J, Jin J, Liu X, Siegfried JM, Di YP. K-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation. Anticancer Res. 2011;31:2877–82.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Gealy R, Zhang L, Siegfried JM, Luketich JD, Keohavong P. Comparison of mutations in the p53 and K-ras genes in lung carcinomas from smoking and nonsmoking women. Cancer Epidemiol Biomark Prev. 1999;8:297–302.Google Scholar
  73. 73.
    Mumford JL, He XZ, Chapman RS, Cao SR, Harris DB, Li XM, Xian YL, Jiang WZ, Xu CW, Chuang JC, et al. Lung cancer and indoor air pollution in Xuan Wei, China. Science. 1987;235:217–20.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Lin H, Ning B, Li J, Ho SC, Huss A, Vermeulen R, Tian L. Lung cancer mortality among women in Xuan Wei, China: a comparison of spatial clustering detection methods. Asia Pac J Public Health. 2015;27:NP392–401.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Bonner MR, Shen M, Liu CS, Divita M, He X, Lan Q. Mitochondrial DNA content and lung cancer risk in Xuan Wei, China. Lung Cancer. 2009;63:331–4.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Keohavong P, Lan Q, Gao WM, Zheng KC, Mady HH, Melhem MF, Mumford JL. Detection of p53 and K-ras mutations in sputum of individuals exposed to smoky coal emissions in Xuan Wei County, China. Carcinogenesis. 2005;26:303–8.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Mumford JL, Li X, Hu F, Lu XB, Chuang JC. Human exposure and dosimetry of polycyclic aromatic hydrocarbons in urine from Xuan Wei, China with high lung cancer mortality associated with exposure to unvented coal smoke. Carcinogenesis. 1995;16:3031–6.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:e17.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Liu SY, Sun H, Zhou JY, Jie GL, Xie Z, Shao Y, Zhang X, Ye JY, Chen CX, Zhang XC, Zhou Q, Yang JJ, Wu YL. Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients. Biomarker Res. 2020;8:22.CrossRefGoogle Scholar
  80. 80.
    Svaton M, Fiala O, Pesek M, Bortlicek Z, Minarik M, Benesova L, Topolcan O. The prognostic role of KRAS mutation in patients with advanced NSCLC treated with second- or third-line chemotherapy. Anticancer Res. 2016;36:1077–82.PubMedGoogle Scholar
  81. 81.
    Nadal E, Chen G, Prensner JR, Shiratsuchi H, Sam C, Zhao L, Kalemkerian GP, Brenner D, Lin J, Reddy RM, Chang AC, Capella G, Cardenal F, Beer DG, Ramnath N. KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J Thorac Oncol. 2014;9:1513–22.PubMedCrossRefGoogle Scholar
  82. 82.
    Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J, Diao L, Coombes KR, Chen L, Zhang S, Abdelmelek MF, Tang X, Papadimitrakopoulou V, Minna JD, Lippman SM, Hong WK, Herbst RS, Wistuba II, Heymach JV, Powis G. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst. 2012;104:228–39.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, Jacks T, Tuveson DA. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001;15:3243–8.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Keohavong P, DeMichele MA, Melacrinos AC, Landreneau RJ, Weyant RJ, Siegfried JM. Detection of K-ras mutations in lung carcinomas: relationship to prognosis. Clin Cancer Res. 1996;2:411–8.PubMedGoogle Scholar
  85. 85.
    Shepherd FA, Domerg C, Hainaut P, Janne PA, Pignon JP, Graziano S, Douillard JY, Brambilla E, Le Chevalier T, Seymour L, Bourredjem A, Le Teuff G, Pirker R, Filipits M, Rosell R, Kratzke R, Bandarchi B, Ma X, Capelletti M, Soria JC, Tsao MS. Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol. 2013;31:2173–81.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Yu HA, Sima CS, Shen R, Kass S, Gainor J, Shaw A, Hames M, Iams W, Aston J, Lovly CM, Horn L, Lydon C, Oxnard GR, Kris MG, Ladanyi M, Riely GJ. Prognostic impact of KRAS mutation subtypes in 677 patients with metastatic lung adenocarcinomas. J Thorac Oncol. 2015;10:431–7.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Ji H, Houghton AM, Mariani TJ, Perera S, Kim CB, Padera R, Tonon G, McNamara K, Marconcini LA, Hezel A, El-Bardeesy N, Bronson RT, Sugarbaker D, Maser RS, Shapiro SD, Wong KK. K-ras activation generates an inflammatory response in lung tumors. Oncogene. 2006;25:2105–12.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001;410:1111–6.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Meuwissen R, Linn SC, van der Valk M, Mooi WJ, Berns A. Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene. Oncogene. 2001;20:6551–8.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A, Varmus HE. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 2001;15:3249–62.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M, Campuzano V, Barbacid M. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell. 2003;4:111–20.PubMedCrossRefGoogle Scholar
  92. 92.
    Sato M, Vaughan MB, Girard L, Peyton M, Lee W, Shames DS, Ramirez RD, Sunaga N, Gazdar AF, Shay JW, Minna JD. Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells. Cancer Res. 2006;66:2116–28.PubMedCrossRefGoogle Scholar
  93. 93.
    Iwanaga K, Yang Y, Raso MG, Ma L, Hanna AE, Thilaganathan N, Moghaddam S, Evans CM, Li H, Cai WW, Sato M, Minna JD, Wu H, Creighton CJ, Demayo FJ, Wistuba II, Kurie JM. Pten inactivation accelerates oncogenic K-ras-initiated tumorigenesis in a mouse model of lung cancer. Cancer Res. 2008;68:1119–27.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kinoshita H, Hayakawa Y, Konishi M, Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S, Nakagawa H, Ikenoue T, Ushiku T, Fukayama M, Hirata Y, Koike K. Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium. J Pathol. 2019;247:35–47.PubMedCrossRefGoogle Scholar
  95. 95.
    Lee HY, Srinivas H, Xia D, Lu Y, Superty R, LaPushin R, Gomez-Manzano C, Gal AM, Walsh GL, Force T, Ueki K, Mills GB, Kurie JM. Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J Biol Chem. 2003;278:23630–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Yanagi S, Kishimoto H, Kawahara K, Sasaki T, Sasaki M, Nishio M, Yajima N, Hamada K, Horie Y, Kubo H, Whitsett JA, Mak TW, Nakano T, Nakazato M, Suzuki A. Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest. 2007;117:2929–40.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004;18:2195–224.PubMedCrossRefGoogle Scholar
  98. 98.
    Yamamoto Y, Gaynor RB. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci. 2004;29:72–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Perkins ND. The diverse and complex roles of NF-kappaB subunits in cancer. Nat Rev Cancer. 2012;12:121–32.PubMedCrossRefGoogle Scholar
  100. 100.
    Stathopoulos GT, Sherrill TP, Cheng DS, Scoggins RM, Han W, Polosukhin VV, Connelly L, Yull FE, Fingleton B, Blackwell TS. Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci U S A. 2007;104:18514–9.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Hao S, Li S, Wang J, Yan Y, Ai X, Zhang J, Ren Y, Wu T, Liu L, Wang C. Phycocyanin exerts anti-proliferative effects through down-regulating TIRAP/NF-kappaB activity in human non-small cell lung cancer cells. Cell. 2019;8:588.CrossRefGoogle Scholar
  102. 102.
    Zhou L, Jiang Y, Liu X, Li L, Yang X, Dong C, Liu X, Lin Y, Li Y, Yu J, He R, Huang S, Liu G, Zhang Y, Jeong LS, Hoffman RM, Jia L. Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-kappaB-CCL2 signaling in lung cancer. Oncogene. 2019;38:5792–804.PubMedCrossRefGoogle Scholar
  103. 103.
    Rasmi RR, Sakthivel KM, Guruvayoorappan C. NF-kappaB inhibitors in treatment and prevention of lung cancer. Biomed Pharmacother. 2020;130:110569.PubMedCrossRefGoogle Scholar
  104. 104.
    Deng S, Ramos-Castaneda M, Velasco WV, Clowers MJ, Gutierrez BA, Noble O, Dong Y, Zarghooni M, Alvarado L, Caetano MS, Yang S, Ostrin EJ, Behrens C, Wistuba II, Stabile LP, Kadara H, Watowich SS, Moghaddam SJ. Interplay between estrogen and Stat3/NF-kappaB driven immunomodulation in lung cancer. Carcinogenesis. 2020;41(11):1529–42.PubMedCrossRefGoogle Scholar
  105. 105.
    Basseres DS, Ebbs A, Levantini E, Baldwin AS. Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res. 2010;70:3537–46.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Mayo MW, Wang CY, Cogswell PC, Rogers-Graham KS, Lowe SW, Der CJ, Baldwin AS Jr. Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science. 1997;278:1812–5.PubMedCrossRefGoogle Scholar
  107. 107.
    Novitskiy SV, Zaynagetdinov R, Vasiukov G, Gutor S, Han W, Serezani A, Matafonov A, Gleaves LA, Sherrill TP, Polosukhin VV, Blackwell TS. Gas6/MerTK signaling is negatively regulated by NF-kappaB and supports lung carcinogenesis. Oncotarget. 2019;10:7031–42.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Meylan E, Dooley AL, Feldser DM, Shen L, Turk E, Ouyang C, Jacks T. Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature. 2009;462:104–7.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Zaynagetdinov R, Stathopoulos GT, Sherrill TP, Cheng DS, McLoed AG, Ausborn JA, Polosukhin VV, Connelly L, Zhou W, Fingleton B, Peebles RS, Prince LS, Yull FE, Blackwell TS. Epithelial nuclear factor-kappaB signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes. Oncogene. 2012;31:3164–76.PubMedCrossRefGoogle Scholar
  110. 110.
    Zaynagetdinov R, Sherrill TP, Gleaves LA, Hunt P, Han W, McLoed AG, Saxon JA, Tanjore H, Gulleman PM, Young LR, Blackwell TS. Chronic NF-kappaB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs. Oncotarget. 2016;7:5470–82.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Allavena P, Garlanda C, Borrello MG, Sica A, Mantovani A. Pathways connecting inflammation and cancer. Curr Opin Genet Dev. 2008;18:3–10.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefGoogle Scholar
  113. 113.
    Du C, Wang Y. The immunoregulatory mechanisms of carcinoma for its survival and development. J Exp Clin Cancer Res. 2011;30:12.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Wang D, DuBois RN. Immunosuppression associated with chronic inflammation in the tumor microenvironment. Carcinogenesis. 2015;36:1085–93.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Witschi H, Williamson D, Lock S. Enhancement of urethan tumorigenesis in mouse lung by butylated hydroxytoluene. J Natl Cancer Inst. 1977;58:301–5.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Malkinson AM, Beer DS. Major effect on susceptibility to urethan-induced pulmonary adenoma by a single gene in BALB/cBy mice. J Natl Cancer Inst. 1983;70:931–6.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Malkinson AM, Koski KM, Evans WA, Festing MF. Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene. Cancer Res. 1997;57:2832–4.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Bauer AK, Dwyer-Nield LD, Hankin JA, Murphy RC, Malkinson AM. The lung tumor promoter, butylated hydroxytoluene (BHT), causes chronic inflammation in promotion-sensitive BALB/cByJ mice but not in promotion-resistant CXB4 mice. Toxicology. 2001;169:1–15.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Adamson IY, Bowden DH, Cote MG, Witschi H. Lung injury induced by butylated hydroxytoluene: cytodynamic and biochemical studies in mice. Lab Investig. 1977;36:26–32.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Miller AC, Dwyer LD, Auerbach CE, Miley FB, Dinsdale D, Malkinson AM. Strain-related differences in the pneumotoxic effects of chronically administered butylated hydroxytoluene on protein kinase C and calpain. Toxicology. 1994;90:141–59.PubMedCrossRefGoogle Scholar
  121. 121.
    Matzinger SA, Gunning WT, You M, Castonguay A. Ki-ras mutations in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-initiated and butylated hydroxytoluene-promoted lung tumors in A/J mice. Mol Carcinog. 1994;11:42–8.PubMedCrossRefGoogle Scholar
  122. 122.
    Wang X, Witschi H. Mutations of the Ki-ras protooncogene in 3-methylcholanthrene and urethan-induced and butylated hydroxytoluene-promoted lung tumors of strain A/J and SWR mice. Cancer Lett. 1995;91:33–9.PubMedCrossRefGoogle Scholar
  123. 123.
    Freire J, Ajona D, de Biurrun G, Agorreta J, Segura V, Guruceaga E, Bleau AM, Pio R, Blanco D, Montuenga LM. Silica-induced chronic inflammation promotes lung carcinogenesis in the context of an immunosuppressive microenvironment. Neoplasia. 2013;15:913–24.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Lakatos HF, Burgess HA, Thatcher TH, Redonnet MR, Hernady E, Williams JP, Sime PJ. Oropharyngeal aspiration of a silica suspension produces a superior model of silicosis in the mouse when compared to intratracheal instillation. Exp Lung Res. 2006;32:181–99.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32:605–44.CrossRefGoogle Scholar
  126. 126.
    Park HY, Kang D, Shin SH, Yoo KH, Rhee CK, Suh GY, Kim H, Shim YM, Guallar E, Cho J, Kwon OJ. Chronic obstructive pulmonary disease and lung cancer incidence in never smokers: a cohort study. Thorax. 2020;75:506–9.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Lee SY, Choi YJ, Seo JH, Lee SY, Kim JS, Kang EJ. Pulmonary function is implicated in the prognosis of metastatic non-small cell lung cancer but not in extended disease small cell lung cancer. J Thorac Dis. 2019;11:4562–72.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Caramori G, Ruggeri P, Mumby S, Ieni A, Lo Bello F, Chimankar V, Donovan C, Ando F, Nucera F, Coppolino I, Tuccari G, Hansbro PM, Adcock IM. Molecular links between COPD and lung cancer: new targets for drug discovery? Expert Opin Ther Targets. 2019;23:539–53.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Moghaddam SJ, Clement CG, De la Garza MM, Zou X, Travis EL, Young HW, Evans CM, Tuvim MJ, Dickey BF. Haemophilus influenzae lysate induces aspects of the chronic obstructive pulmonary disease phenotype. Am J Respir Cell Mol Biol. 2008;38:629–38.PubMedCrossRefGoogle Scholar
  130. 130.
    Moghaddam SJ, Li H, Cho SN, Dishop MK, Wistuba II, Ji L, Kurie JM, Dickey BF, Demayo FJ. Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model. Am J Respir Cell Mol Biol. 2009;40:443–53.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Barta P, Van Pelt C, Men T, Dickey BF, Lotan R, Moghaddam SJ. Enhancement of lung tumorigenesis in a Gprc5a knockout mouse by chronic extrinsic airway inflammation. Mol Cancer. 2012;11:4.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Tao Q, Fujimoto J, Men T, Ye X, Deng J, Lacroix L, Clifford JL, Mao L, Van Pelt CS, Lee JJ, Lotan D, Lotan R. Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene. J Natl Cancer Inst. 2007;99:1668–82.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    De la Garza MM, Cumpian AM, Daliri S, Castro-Pando S, Umer M, Gong L, Khosravi N, Caetano MS, Ramos-Castaneda M, Flores AG, Beltran EC, Tran HT, Tuvim MJ, Ostrin EJ, Dickey BF, Evans CM, Moghaddam SJ. COPD-type lung inflammation promotes K-ras mutant lung cancer through epithelial HIF-1alpha mediated tumor angiogenesis and proliferation. Oncotarget. 2018;9:32972–83.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Hasday JD, Bascom R, Costa JJ, Fitzgerald T, Dubin W. Bacterial endotoxin is an active component of cigarette smoke. Chest. 1999;115:829–35.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Rathinam VAK, Zhao Y, Shao F. Innate immunity to intracellular LPS. Nat Immunol. 2019;20:527–33.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Yao X, Dong G, Zhu Y, Yan F, Zhang H, Ma Q, Fu X, Li X, Zhang Q, Zhang J, Shi H, Ning Z, Dai J, Li Z, Li C, Wang B, Ming J, Yang Y, Hong F, Meng X, Xiong H, Si C. Leukadherin-1-mediated activation of CD11b inhibits LPS-induced pro-inflammatory response in macrophages and protects mice against endotoxic shock by blocking LPS-TLR4 interaction. Front Immunol. 2019;10:215.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Pera T, Zuidhof A, Valadas J, Smit M, Schoemaker RG, Gosens R, Maarsingh H, Zaagsma J, Meurs H. Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD. Eur Respir J. 2011;38:789–96.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Melkamu T, Qian X, Upadhyaya P, O’Sullivan MG, Kassie F. Lipopolysaccharide enhances mouse lung tumorigenesis: a model for inflammation-driven lung cancer. Vet Pathol. 2013;50:895–902.Google Scholar
  139. 139.
    Liu CH, Chen Z, Chen K, Liao FT, Chung CE, Liu X, Lin YC, Keohavong P, Leikauf GD, Di YP. Lipopolysaccharide-mediated chronic inflammation promotes tobacco carcinogen–induced lung cancer and determines the efficacy of immunotherapy. Cancer Res. 2020;  https://doi.org/10.1158/0008-5472.CAN-20-1994, PMID: 33122306.
  140. 140.
    Kiyan Y, Tkachuk S, Kurselis K, Shushakova N, Stahl K, Dawodu D, Kiyan R, Chichkov B, Haller H. Heparanase-2 protects from LPS-mediated endothelial injury by inhibiting TLR4 signalling. Sci Rep. 2019;9:13591.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Tsukamoto H, Takeuchi S, Kubota K, Kobayashi Y, Kozakai S, Ukai I, Shichiku A, Okubo M, Numasaki M, Kanemitsu Y, Matsumoto Y, Nochi T, Watanabe K, Aso H, Tomioka Y. Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent toll-like receptor 4 internalization and LPS-induced TBK1-IKK-IRF3 axis activation. J Biol Chem. 2018;293:10186–201.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    An J, Kim SH, Hwang D, Lee KE, Kim MJ, Yang EG, Kim SY, Chung HS. Caspase-4 disaggregates lipopolysaccharide micelles via LPS-CARD interaction. Sci Rep. 2019;9:826.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Woods PS, Kimmig LM, Meliton AY, Sun KA, Tian Y, O’Leary EM, Gokalp GA, Hamanaka RB, Mutlu GM. Tissue-resident alveolar macrophages do not rely on glycolysis for LPS-induced inflammation. Am J Respir Cell Mol Biol. 2020;62:243–55.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Mracek T, Cannon B, Houstek J. IL-1 and LPS but not IL-6 inhibit differentiation and downregulate PPAR gamma in brown adipocytes. Cytokine. 2004;26:9–15.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Metwally H, Tanaka T, Li S, Parajuli G, Kang S, Hanieh H, Hashimoto S, Chalise JP, Gemechu Y, Standley DM, Kishimoto T. Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production. Sci Signal. 2020;13(624):eaay0574. https://doi.org/10.1126/scisignal.aay0574.
  146. 146.
    Wang J, Yan X, Nesengani LT, Ding H, Yang L, Lu W. LPS-induces IL-6 and IL-8 gene expression in bovine endometrial cells “through DNA methylation”. Gene. 2018;677:266–72.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Lee HR, Shin SH, Kim JH, Sohn KY, Yoon SY, Kim JW. 1-Palmitoyl-2-Linoleoyl-3-acetyl-rac-glycerol (PLAG) rapidly resolves LPS-induced acute lung injury through the effective control of neutrophil recruitment. Front Immunol. 2019;10:2177.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Amison RT, Arnold S, O’Shaughnessy BG, Cleary SJ, Ofoedu J, Idzko M, Page CP, Pitchford SC. Lipopolysaccharide (LPS) induced pulmonary neutrophil recruitment and platelet activation is mediated via the P2Y1 and P2Y14 receptors in mice. Pulm Pharmacol Ther. 2017;45:62–8.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Wang X, Qin W, Song M, Zhang Y, Sun B. Exogenous carbon monoxide inhibits neutrophil infiltration in LPS-induced sepsis by interfering with FPR1 via p38 MAPK but not GRK2. Oncotarget. 2016;7:34250–65.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Elizur A, Adair-Kirk TL, Kelley DG, Griffin GL, Demello DE, Senior RM. Tumor necrosis factor-alpha from macrophages enhances LPS-induced clara cell expression of keratinocyte-derived chemokine. Am J Respir Cell Mol Biol. 2008;38:8–15.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Xiang Y, Zhang S, Lu J, Zhang W, Cai M, Qiu D, Cai D. USP9X promotes LPS-induced pulmonary epithelial barrier breakdown and hyperpermeability by activating an NF-kappaBp65 feedback loop. Am J Physiol Cell Physiol. 2019;317:C534–43.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Zeng M, Huang C, Zheng H, Chen Q, He W, Deng Y. Effects of ghrelin on iNOS-derived NO promoted LPS-induced pulmonary alveolar epithelial A549 cells apoptosis. Cell Physiol Biochem. 2018;49:1840–55.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Bein K, Di Giuseppe M, Mischler SE, Ortiz LA, Leikauf GD. LPS-treated macrophage cytokines repress surfactant protein-B in lung epithelial cells. Am J Respir Cell Mol Biol. 2013;49:306–15.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res. 2000;60:184–90.PubMedGoogle Scholar
  155. 155.
    Pao PC, Patnaik D, Watson LA, Gao F, Pan L, Wang J, Adaikkan C, Penney J, Cam HP, Huang WC, Pantano L, Lee A, Nott A, Phan TX, Gjoneska E, Elmsaouri S, Haggarty SJ, Tsai LH. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nat Commun. 2020;11:2484.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Dutto I, Scalera C, Tillhon M, Ticli G, Passaniti G, Cazzalini O, Savio M, Stivala LA, Gervasini C, Larizza L, Prosperi E. Mutations in CREBBP and EP300 genes affect DNA repair of oxidative damage in Rubinstein-Taybi syndrome cells. Carcinogenesis. 2020;41:257–66.PubMedCrossRefGoogle Scholar
  157. 157.
    Admiraal SJ, Eyler DE, Baldwin MR, Brines EM, Lohans CT, Schofield CJ, O’Brien PJ. Expansion of base excision repair compensates for a lack of DNA repair by oxidative dealkylation in budding yeast. J Biol Chem. 2019;294:13629–37.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Higinbotham KG, Rice JM, Diwan BA, Kasprzak KS, Reed CD, Perantoni AO. GGT to GTT transversions in codon 12 of the K-ras oncogene in rat renal sarcomas induced with nickel subsulfide or nickel subsulfide/iron are consistent with oxidative damage to DNA. Cancer Res. 1992;52:4747–51.PubMedGoogle Scholar
  159. 159.
    Du MQ, Carmichael PL, Phillips DH. Induction of activating mutations in the human c-Ha-ras-1 proto-oncogene by oxygen free radicals. Mol Carcinog. 1994;11:170–5.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Environmental and Occupational health, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA

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