Skip to main content

Advertisement

SpringerLink
Log in

PI3K-γ Inhibition Ameliorates Acute Lung Injury Through Regulation of IκBα/NF-κB Pathway and Innate Immune Responses

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Background

Acute lung injury (ALI) is a devastating disorder of the lung by various causes and its cardinal features are tissue inflammation, pulmonary edema, low lung compliance, and widespread capillary leakage. Among phosphoinositide 3-kinases (PI3Ks), PI3K-γ isoform has been shown to play an important role in a number of immune/inflammatory responses.

Methods

We investigated the role of PI3K-γ and its molecular basis in lipopolysaccharide (LPS)-induced ALI using a selective inhibitor for PI3K-γ, AS 605240, and LPS-treated C57BL/6 mice.

Results

Treatment of mice with LPS showed an increase of lung inflammation and vascular leakage. Production of reactive oxygen species (ROS), interleukin (IL)-1β, tumor necrosis factor-α, and IL-4, adhesion molecule, and vascular endothelial growth factor (VEGF) was also increased. Administration of AS 605240 to LPS-treated mice markedly reduced the pathophysiological features of ALI and the increased production of ROS, cytokines, adhesion molecule, and VEGF in the lung. Our results also showed that treatment of mice with LPS activates nuclear factor-κB (NF-κB) and degradation of inhibitory κBα (IκBα) through PI3K-γ. Additionally, infiltration of dendritic cells (DCs) and expression of toll-like receptor 4 (TLR4) were significantly increased in the lung of LPS-treated mice, and inhibition of PI3K-γ reduced the infiltration of DCs and TLR4 expression in the lung.

Conclusions

These results indicate that PI3K-γ is critically involved in LPS-induced ALI by regulating IκBα/NF-κB pathway and innate immune responses. Based on our data, we suggest that PI3K-γ isoform is a promising target for the treatment of ALI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. He Z, Zhu Y, Jiang H. Toll-like receptor 4 mediates lipopolysaccharide-induced collagen secretion by phosphoinositide3-kinase-Akt pathway in fibroblasts during acute lung injury. J Recept Signal Transduct Res. 2009;29:119–25.

    Article  PubMed  CAS  Google Scholar 

  2. Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, et al. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun. 2006;351:883–9.

    Article  PubMed  CAS  Google Scholar 

  3. Park HS, Kim SR, Lee YC. Impact of oxidative stress on lung diseases. Respirology. 2009;14:27–38.

    Article  PubMed  Google Scholar 

  4. Fink MP. Reactive oxygen species as mediators of organ dysfunction caused by sepsis, acute respiratory distress syndrome, or hemorrhagic shock: potential benefits of resuscitation with Ringer’s ethyl pyruvate solution. Curr Opin Clin Nutr Metab Care. 2002;5:167–74.

    Article  PubMed  CAS  Google Scholar 

  5. Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–49.

    Article  PubMed  CAS  Google Scholar 

  6. Fan J, Frey RS, Malik AB. TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase. J Clin Invest. 2003;112:1234–43.

    PubMed  CAS  Google Scholar 

  7. Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae YS. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. J Immunol. 2004;173:3589–93.

    PubMed  CAS  Google Scholar 

  8. Henderson Jr WR, Chi EY, Teo JL, Nguyen C, Kahn M. A small molecule inhibitor of redox-regulated NF-kappa B and activator protein-1 transcription blocks allergic airway inflammation in a mouse asthma model. J Immunol. 2002;169:5294–9.

    PubMed  Google Scholar 

  9. Yum HK, Arcaroli J, Kupfner J, Shenkar R, Penninger JM, Sasaki T, et al. Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury. J Immunol. 2001;167:6601–8.

    PubMed  CAS  Google Scholar 

  10. Hua F, Ha T, Ma J, Li Y, Kelley J, Gao X, et al. Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J Immunol. 2007;178:7317–24.

    PubMed  CAS  Google Scholar 

  11. Medina-Tato DA, Ward SG, Watson ML. Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond. Immunology. 2007;121:448–61.

    Article  PubMed  CAS  Google Scholar 

  12. Ward SG, Finan P. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr Opin Pharmacol. 2003;3:426–34.

    Article  PubMed  CAS  Google Scholar 

  13. Barberis L, Hirsch E. Targeting phosphoinositide 3-kinase gamma to fight inflammation and more. Thromb Haemost. 2008;99:279–85.

    PubMed  CAS  Google Scholar 

  14. Park SJ, Min KH, Lee YC. Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma. Respirology. 2008;13:764–71.

    Article  PubMed  Google Scholar 

  15. Reutershan J, Saprito MS, Wu D, Rückle T, Ley K. Phosphoinositide 3-kinase gamma required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung. Eur Respir J. 2010;35:1137–47.

    Article  PubMed  CAS  Google Scholar 

  16. Shang GH, Lin DJ, Xiao W, Jia CQ, Li Y, Wang AH, et al. Ethyl pyruvate reduces mortality in an endotoxin-induced severe acute lung injury mouse model. Respir Res. 2009;10:91.

    Article  PubMed  Google Scholar 

  17. Zerfaoui M, Naura AS, Errami Y, Hans CP, Rezk BM, Park J, et al. Effects of PARP-1 deficiency on airway inflammatory cell recruitment in response to LPS or TNF: differential effects on CXCR2 ligands and Duffy antigen receptor for chemokines. J Leukoc Biol. 2009;86:1385–92.

    Article  PubMed  CAS  Google Scholar 

  18. Kim SR, Lee KS, Park HS, Park SJ, Min KH, Moon H, et al. HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40:2858–69.

    Article  PubMed  CAS  Google Scholar 

  19. Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science. 1995;270:296–9.

    Article  PubMed  CAS  Google Scholar 

  20. Sung MJ, Kim DH, Jung YJ, Kang KP, Lee AS, Lee S, et al. Genistein protects the kidney from cisplatin-induced injury. Kidney Int. 2008;74:1538–47.

    Article  PubMed  CAS  Google Scholar 

  21. Sun L, Chen T, Wang X, Chen Y, Wei X. Bufalin induces reactive oxygen species dependent Bax translocation and apoptosis in ASTC-a-1 cells. Evid Based Complement Alternat Med. 2011. doi:10.1093/ecam/nep082.

  22. Kim TB, Kim SY, Moon KA, Park CS, Jang MK, Yun ES, et al. Five-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates poly (I:C)-induced airway inflammation in a murine model of asthma. Clin Exp Allergy. 2007;37:1709–19.

    Article  PubMed  CAS  Google Scholar 

  23. Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15:410–6.

    Article  PubMed  CAS  Google Scholar 

  24. Wheeler AP, Bernard GR. Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet. 2007;369:1553–64.

    Article  PubMed  Google Scholar 

  25. McCabe AJ, Dowhy M, Holm BA, Glick PL. Myeloperoxidase activity as a lung injury marker in the lamb model of congenital diaphragmatic hernia. J Pediatr Surg. 2001;36:334–7.

    Article  PubMed  CAS  Google Scholar 

  26. Rückle T, Schwarz MK, Rommel C. PI3Kγ inhibition: towards an ‘aspirin of the 21st century’? Nat Rev Drug Discov. 2006;5:903–18.

    Article  PubMed  Google Scholar 

  27. Venable JD, Ameriks MK, Blevitt JM, Thurmond RL, Fung-Leung WP. Phosphoinositide 3-kinase gamma (PI3Kgamma) inhibitors for the treatment of inflammation and autoimmune disease. Recent Pat Inflamm Allergy Drug Discov. 2010;4:1–15.

    Article  PubMed  CAS  Google Scholar 

  28. Lionetti V, Lisi A, Patrucco E, De Giuli P, Milazzo MG, Ceci S, et al. Lack of phosphoinositide 3-kinase-γ attenuates ventilator-induced lung injury. Crit Care Med. 2006;34:134–41.

    Article  PubMed  CAS  Google Scholar 

  29. Uhlig U, Fehrenbach H, Lachmann RA, Goldmann T, Lachmann B, Vollmer E, et al. Phosphoinositide 3-OH kinase inhibition prevents ventilation-induced lung cell activation. Am J Respir Crit Care Med. 2004;169:201–8.

    Article  PubMed  Google Scholar 

  30. Park HS, Kim SY, Kim SR, Lee YC. Targeting abnormal airway vascularity as a therapeutical strategy in asthma. Respirology. 2010;15:459–71.

    Article  PubMed  Google Scholar 

  31. Kuroki M, Voest EE, Amano S, Beerepoot LV, Takashima S, Tolentino M, et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest. 1996;98:1667–75.

    Article  PubMed  CAS  Google Scholar 

  32. Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax. 1998;53:601–12.

    Article  PubMed  CAS  Google Scholar 

  33. Tong Q, Zheng L, Lin L, Wang D, Huang C, Li D. VEGF is upregulated by hypoxia-induced mitogenic factor via the PI-3 K/Akt-NF-kappaB signaling pathway. Respir Res. 2006;7:37.

    Article  PubMed  Google Scholar 

  34. Montefort S, Holgate ST. Adhesion molecules and their role in inflammation. Respir Med. 1991;85:91–9.

    Article  PubMed  CAS  Google Scholar 

  35. Moser R, Fehr J, Bruijnzeel PL. IL-4 controls the selective endothelium-driven transmigration of eosinophils from allergic individuals. J Immunol. 1992;149:1432–8.

    PubMed  CAS  Google Scholar 

  36. D’Andrea A, Ma X, Aste-Amezaga M, Paganin C, Trinchieri G. Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production. J Exp Med. 1995;181:537–46.

    Article  PubMed  Google Scholar 

  37. Kambayashi T, Jacob CO, Strassmann G. IL-4 and IL-13 modulate IL-10 release in endotoxin-stimulated murine peritoneal mononuclear phagocytes. Cell Immunol. 1996;171:153–8.

    Article  PubMed  CAS  Google Scholar 

  38. Roy S, Charboneau R, Melnyk D, Barke RA. Interleukin-4 regulates macrophage interleukin-12 protein synthesis through a c-fos mediated mechanism. Surgery. 2000;128:219–24.

    Article  PubMed  CAS  Google Scholar 

  39. Major J, Fletcher JE, Hamilton TA. IL-4 pretreatment selectively enhances cytokine and chemokine production in lipopolysaccharide-stimulated mouse peritoneal macrophages. J Immunol. 2002;168:2456–63.

    PubMed  CAS  Google Scholar 

  40. Reddy SA, Huang JH, Liao WS. Phosphatidylinositol 3-kinase as a mediator of TNF-induced NF-kappa B activation. J Immunol. 2000;164:1355–63.

    PubMed  CAS  Google Scholar 

  41. Toker A. Protein kinases as mediators of phosphoinositide 3-kinase signaling. Mol Pharmacol. 2000;57:652–8.

    PubMed  CAS  Google Scholar 

  42. Frey RS, Gao X, Javaid K, Siddiqui SS, Rahman A, Malik AB. Phosphatidylinositol 3-kinase gamma signaling through protein kinase Czeta induces NADPH oxidase-mediated oxidant generation and NF-kappaB activation in endothelial cells. J Biol Chem. 2006;281:16128–38.

    Article  PubMed  CAS  Google Scholar 

  43. Gukovsky I, Cheng JH, Nam KJ, Lee OT, Lugea A, Fischer L, et al. Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells. Gastroenterology. 2004;126:554–66.

    Article  PubMed  CAS  Google Scholar 

  44. Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol. 1997;9:10–6.

    Article  PubMed  CAS  Google Scholar 

  45. Steinman RM, Inaba K. Myeloid dendritic cells. J Leukoc Biol. 1999;66:205–8.

    PubMed  CAS  Google Scholar 

  46. Togbe D, Schnyder-Candrian S, Schnyder B, Couillin I, Maillet I, Bihl F, et al. TLR4 gene dosage contributes to endotoxin-induced acute respiratory inflammation. J Leukoc Biol. 2006;80:451–7.

    Article  PubMed  CAS  Google Scholar 

  47. Bhattacharyya S, Dudeja PK, Tobacman JK. Lipopolysaccharide activates NF-kappaB by TLR4-Bcl10-dependent and independent pathways in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2008;295:G784–90.

    Article  PubMed  CAS  Google Scholar 

  48. Xu H, Su Z, Wu J, Yang M, Penninger JM, Martin CM, et al. The alarmin cytokine, high mobility group box 1, is produced by viable cardiomyocytes and mediates the lipopolysaccharide-induced myocardial dysfunction via a TLR4/phosphatidylinositol 3-kinase gamma pathway. J Immunol. 2010;184:1492–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A084144).

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea

    Dong Im Kim, So Ri Kim, Hee Jung Kim, Su Jeong Lee, Heung Bum Lee, Seoung Ju Park, Mie-Jae Im & Yong Chul Lee

Authors
  1. Dong Im Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. So Ri Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hee Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Su Jeong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heung Bum Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seoung Ju Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mie-Jae Im
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yong Chul Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Chul Lee.

Additional information

Dong Im Kim and So Ri Kim contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 216 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, D.I., Kim, S.R., Kim, H.J. et al. PI3K-γ Inhibition Ameliorates Acute Lung Injury Through Regulation of IκBα/NF-κB Pathway and Innate Immune Responses. J Clin Immunol 32, 340–351 (2012). https://doi.org/10.1007/s10875-011-9628-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9628-1

Keywords

Search

Navigation