Obesity Exacerbates Influenza-induced Respiratory Disease Via the Arachidonic Acid-p38 MAPK Pathway

Overview

Journal Front Pharmacol

Date 2023 Sep 8

PMID 37680710

Authors

Ravishankar Chandrasekaran

Carolyn R Morris

Isabella M Butzirus

Zoe F Mark

Amit Kumar

Dhemerson Souza De Lima

Nirav Daphtary

Minara Aliyeva

Matthew E Poynter

Vikas Anathy

Anne E Dixon

Affiliations

Soon will be listed here.

Abstract

Obesity is a risk factor for severe influenza, and asthma exacerbations caused by respiratory viral infections. We investigated mechanisms that increase the severity of airway disease related to influenza in obesity using cells derived from obese and lean individuals, and and models. Primary human nasal epithelial cells (pHNECs) derived from obese compared with lean individuals developed increased inflammation and injury in response to influenza A virus (IAV). Obese mice infected with influenza developed increased airway inflammation, lung injury and elastance, but had a decreased interferon response, compared with lean mice. Lung arachidonic acid (AA) levels increased in obese mice infected with IAV; arachidonic acid increased inflammatory cytokines and injury markers in response to IAV in human bronchial epithelial (HBE) cells. Obesity in mice, and AA in HBE cells, increased activation of p38 MAPK signaling following IAV infection; inhibiting this pathway attenuated inflammation, injury and tissue elastance responses, and improved survival. In summary, obesity increases disease severity in response to influenza infection through activation of the p38 MAPK pathway in response to altered arachidonic acid signaling.

Citing Articles

Elevated body mass index is not significantly associated with reduced influenza vaccine effectiveness.

King J, Nguyen H, Kiniry E, Phillips C, Gaglani M, Martin E Sci Rep. 2024; 14(1):21466.

PMID: 39271784 PMC: 11399117. DOI: 10.1038/s41598-024-72081-z.

The Impact of Obesity on the Host-Pathogen Interaction with Influenza Viruses - Novel Insights: Narrative Review.

Miron V, Draganescu A, Pitigoi D, Arama V, Streinu-Cercel A, Sandulescu O Diabetes Metab Syndr Obes. 2024; 17:769-777.

PMID: 38371386 PMC: 10874191. DOI: 10.2147/DMSO.S434115.

References

Rutting S, Xenaki D, Lau E, Horvat J, Wood L, Hansbro P . Dietary omega-6, but not omega-3, polyunsaturated or saturated fatty acids increase inflammation in primary lung mesenchymal cells. Am J Physiol Lung Cell Mol Physiol. 2018; 314(6):L922-L935. DOI: 10.1152/ajplung.00438.2017. View

Meineke R, Rimmelzwaan G, Elbahesh H . Influenza Virus Infections and Cellular Kinases. Viruses. 2019; 11(2). PMC: 6410056. DOI: 10.3390/v11020171. View

van de Sandt C, Kreijtz J, Rimmelzwaan G . Evasion of influenza A viruses from innate and adaptive immune responses. Viruses. 2012; 4(9):1438-76. PMC: 3499814. DOI: 10.3390/v4091438. View

Coulombe F, Jaworska J, Verway M, Tzelepis F, Massoud A, Gillard J . Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages. Immunity. 2014; 40(4):554-68. DOI: 10.1016/j.immuni.2014.02.013. View

Chandrasekharan J, Marginean A, Sharma-Walia N . An insight into the role of arachidonic acid derived lipid mediators in virus associated pathogenesis and malignancies. Prostaglandins Other Lipid Mediat. 2016; 126:46-54. DOI: 10.1016/j.prostaglandins.2016.07.009. View

Milner J, Rebeles J, Dhungana S, Stewart D, Sumner S, Meyers M . Obesity Increases Mortality and Modulates the Lung Metabolome during Pandemic H1N1 Influenza Virus Infection in Mice. J Immunol. 2015; 194(10):4846-59. PMC: 4417391. DOI: 10.4049/jimmunol.1402295. View

Yang S, Pene Dumitrescu T . Population Pharmacokinetics and Pharmacodynamics Modelling of Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome. Drugs R D. 2016; 17(1):145-158. PMC: 5318329. DOI: 10.1007/s40268-016-0161-9. View

Martin E, Archer C, McRoberts J, Kulik J, Thurston T, Lephart P . Epidemiology of severe influenza outcomes among adult patients with obesity in Detroit, Michigan, 2011. Influenza Other Respir Viruses. 2013; 7(6):1004-7. PMC: 3749256. DOI: 10.1111/irv.12115. View

Flerlage T, Boyd D, Meliopoulos V, Thomas P, Schultz-Cherry S . Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract. Nat Rev Microbiol. 2021; 19(7):425-441. PMC: 8023351. DOI: 10.1038/s41579-021-00542-7. View

10.

Fezeu L, Julia C, Henegar A, Bitu J, Hu F, Grobbee D . Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis. Obes Rev. 2011; 12(8):653-9. DOI: 10.1111/j.1467-789X.2011.00864.x. View

11.

Vaillant L, La Ruche G, Tarantola A, Barboza P . Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill. 2009; 14(33). DOI: 10.2807/ese.14.33.19309-en. View

12.

Rutting S, Zakarya R, Bozier J, Xenaki D, Horvat J, Wood L . Dietary Fatty Acids Amplify Inflammatory Responses to Infection through p38 MAPK Signaling. Am J Respir Cell Mol Biol. 2019; 60(5):554-568. DOI: 10.1165/rcmb.2018-0215OC. View

13.

Li J, Jie X, Liang X, Chen Z, Xie P, Pan X . Sinensetin suppresses influenza a virus-triggered inflammation through inhibition of NF-κB and MAPKs signalings. BMC Complement Med Ther. 2020; 20(1):135. PMC: 7200050. DOI: 10.1186/s12906-020-02918-3. View

14.

Chen J, Deng J, Zemans R, Bahmed K, Kosmider B, Zhang M . Age-induced prostaglandin E impairs mitochondrial fitness and increases mortality to influenza infection. Nat Commun. 2022; 13(1):6759. PMC: 9643978. DOI: 10.1038/s41467-022-34593-y. View

15.

Mizumura K, Hashimoto S, Maruoka S, Gon Y, Kitamura N, Matsumoto K . Role of mitogen-activated protein kinases in influenza virus induction of prostaglandin E2 from arachidonic acid in bronchial epithelial cells. Clin Exp Allergy. 2003; 33(9):1244-51. DOI: 10.1046/j.1365-2222.2003.01750.x. View

16.

Yang S, Wang L, Pan X, Liang Y, Zhang Y, Li J . 5-Methoxyflavone-induced AMPKα activation inhibits NF-κB and P38 MAPK signaling to attenuate influenza A virus-mediated inflammation and lung injury in vitro and in vivo. Cell Mol Biol Lett. 2022; 27(1):82. PMC: 9524045. DOI: 10.1186/s11658-022-00381-1. View

17.

Yu J, Sun X, Goie J, Zhang Y . Regulation of Host Immune Responses against Influenza A Virus Infection by Mitogen-Activated Protein Kinases (MAPKs). Microorganisms. 2020; 8(7). PMC: 7409222. DOI: 10.3390/microorganisms8071067. View

18.

Chandrasekaran R, Bruno S, Mark Z, Walzer J, Caffry S, Gold C . Mitoquinone mesylate attenuates pathological features of lean and obese allergic asthma in mice. Am J Physiol Lung Cell Mol Physiol. 2022; 324(2):L141-L153. PMC: 9902225. DOI: 10.1152/ajplung.00249.2022. View

19.

Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Suzuki S . Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice. Biochem Biophys Res Commun. 2019; 513(2):405-411. DOI: 10.1016/j.bbrc.2019.03.211. View

20.

Easterbrook J, Dunfee R, Schwartzman L, Jagger B, Sandouk A, Kash J . Obese mice have increased morbidity and mortality compared to non-obese mice during infection with the 2009 pandemic H1N1 influenza virus. Influenza Other Respir Viruses. 2011; 5(6):418-25. PMC: 3175349. DOI: 10.1111/j.1750-2659.2011.00254.x. View