HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice
Abstract
1. Introduction
2. Materials and Methods
2.1. Experimental Design
2.2. Reagents
2.3. Immunohistochemistry
2.4. Isolation of Lung and Intra-Peritoneal Macrophages
2.5. Generation of Mouse Lung Endothelial Cell Line
2.6. Trans-Endothelial Migration Assay
2.7. Real-Time Polymerase Chain Reaction (RT-PCR)
2.8. Lung Injury Scores
2.9. Bleeding Score
2.10. Flow Cytometry
2.11. BioPlex Cytokine Analysis
2.12. Mouse VEGF Enzyme-Linked Immunosorbent Assay (ELISA)
2.13. Statistical Analysis
3. Results
3.1. Increased Neutrophil Infiltration and Decreased Macrophage Infiltration in Lungs of Human Immunodeficiency Virus 1 Transgenic (HIV-Tg) Mice after LPS Administration
3.2. LPS Injections Induced Higher Levels of Inflammatory Cytokines in HIV-Tg Mice
3.3. Resolution of Lung Leukocytes’ Infiltration after LPS Administration Is Slower in HIV-Tg Mice
3.4. Trans-Endothelial Migration of Macrophages Isolated from HIV-Tg Mice Are Reduced In Vitro
3.5. Administration of HIV-1 Transcription Inhibitor 1E7-03 Improves Trans-Endothelial Macrophages Migration In Vitro and the Levels of Lung Leukocytes Infiltration in HIV-Tg Mice
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
References
- Friis-Moller, N.; Sabin, C.A.; Weber, R.; d’Arminio Monforte, A.; El-Sadr, W.M.; Reiss, P.; Thiebaut, R.; Morfeldt, L.; de Wit, S.; Pradier, C.; et al. Data Collection on Adverse Events of Anti, H.I.V.D.S.G., Combination antiretroviral therapy and the risk of myocardial infarction. New Engl. J. Med. 2003, 349, 1993–2003. [Google Scholar]
- Wand, H.; Calmy, A.; Carey, D.L.; Samaras, K.; Carr, A.; Law, M.G.; Cooper, D.A.; Emery, S.; Committee, I.T.I.C. Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. Aids 2007, 21, 2445–2453. [Google Scholar] [CrossRef] [PubMed]
- Calligaro, G.L.; Gray, D.M. Lung function abnormalities in HIV-infected adults and children. Respirology 2015, 20, 24–32. [Google Scholar] [CrossRef] [PubMed]
- Morris, A.; George, M.P.; Crothers, K.; Huang, L.; Lucht, L.; Kessinger, C.; Kleerup, E.C.; Lung, H.I.V.S. HIV and chronic obstructive pulmonary disease: Is it worse and why? Proc. Am. Thorac. Soc. 2011, 8, 320–325. [Google Scholar] [CrossRef]
- Crothers, K.; Thompson, B.W.; Burkhardt, K.; Morris, A.; Flores, S.C.; Diaz, P.T.; Chaisson, R.E.; Kirk, G.D.; Rom, W.N.; Huang, L.; et al. HIV-associated lung infections and complications in the era of combination antiretroviral therapy. Proc. Am. Thorac. Soc. 2011, 8, 275–281. [Google Scholar] [CrossRef] [PubMed]
- Agusti, A.; Edwards, L.D.; Rennard, S.I.; MacNee, W.; Tal-Singer, R.; Miller, B.E.; Vestbo, J.; Lomas, D.A.; Calverley, P.M.; Wouters, E.; et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: A novel phenotype. PLoS ONE 2012, 7, e37483. [Google Scholar] [CrossRef]
- Decramer, M.; Janssens, W.; Miravitlles, M. Chronic obstructive pulmonary disease. Lancet 2012, 379, 1341–1351. [Google Scholar] [CrossRef]
- Diaz, P.T.; King, M.A.; Pacht, E.R.; Wewers, M.D.; Gadek, J.E.; Nagaraja, H.N.; Drake, J.; Clanton, T.L. Increased susceptibility to pulmonary emphysema among HIV-seropositive smokers. Ann. Intern. Med. 2000, 132, 369–372. [Google Scholar] [CrossRef]
- Pappas, K.; Papaioannou, A.I.; Kostikas, K.; Tzanakis, N. The role of macrophages in obstructive airways disease: Chronic obstructive pulmonary disease and asthma. Cytokine 2013, 64, 613–625. [Google Scholar] [CrossRef]
- Meijer, M.; Rijkers, G.T.; van Overveld, F.J. Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease. Expert Rev. Clin. Immunol. 2013, 9, 1055–1068. [Google Scholar] [CrossRef]
- Stockley, J.A.; Walton, G.M.; Lord, J.M.; Sapey, E. Aberrant neutrophil functions in stable chronic obstructive pulmonary disease: The neutrophil as an immunotherapeutic target. Int. Immunopharmacol. 2013, 17, 1211–1217. [Google Scholar] [CrossRef]
- Attia, E.F.; Akgun, K.M.; Wongtrakool, C.; Goetz, M.B.; Rodriguez-Barradas, M.C.; Rimland, D.; Brown, S.T.; Soo Hoo, G.W.; Kim, J.; Lee, P.J.; et al. Increased risk of radiographic emphysema in HIV is associated with elevated soluble CD14 and nadir CD4. Chest 2014, 146, 1543–1553. [Google Scholar] [CrossRef] [PubMed]
- Fitzpatrick, M.E.; Singh, V.; Bertolet, M.; Lucht, L.; Kessinger, C.; Michel, J.; Logar, A.; Weinman, R.; McMahon, D.; Norris, K.A.; et al. Relationships of pulmonary function, inflammation, and T-cell activation and senescence in an HIV-infected cohort. Aids 2014, 28, 2505–2515. [Google Scholar] [CrossRef] [PubMed]
- Singh, S.; Verma, S.K.; Kumar, S.; Ahmad, M.K.; Nischal, A.; Singh, S.K.; Dixit, R.K. Correlation of severity of chronic obstructive pulmonary disease with potential biomarkers. Immunol. Lett. 2018, 196, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Norris, K.A.; Morris, A.; Patil, S.; Fernandes, E. Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome. Immunol. Res. 2006, 36, 175–187. [Google Scholar] [CrossRef]
- Almodovar, S. The complexity of HIV persistence and pathogenesis in the lung under antiretroviral therapy: Challenges beyond AIDS. Viral Immunol. 2014, 27, 186–199. [Google Scholar] [CrossRef]
- Itescu, S.; Simonelli, P.F.; Winchester, R.J.; Ginsberg, H.S. Human immunodeficiency virus type 1 strains in the lungs of infected individuals evolve independently from those in peripheral blood and are highly conserved in the C-terminal region of the envelope V3 loop. Proc. Natl. Acad. Sci. USA 1994, 91, 11378–11382. [Google Scholar] [CrossRef]
- Twigg, H.L.; Schnizlein-Bick, C.T.; Weiden, M.; Valentine, F.; Wheat, J.; Day, R.B.; Rominger, H.; Zheng, L.; Collman, R.G.; Coombs, R.W.; et al. Measurement of antiretroviral drugs in the lungs of HIV-infected patients. HIV Ther. 2010, 4, 247–251. [Google Scholar] [CrossRef]
- Twigg, H.L., 3rd; Iwamoto, G.K.; Soliman, D.M. Role of cytokines in alveolar macrophage accessory cell function in HIV-infected individuals. J. Immunol. 1992, 149, 1462–1469. [Google Scholar]
- Buhl, R.; Jaffe, H.A.; Holroyd, K.J.; Borok, Z.; Roum, J.H.; Mastrangeli, A.; Wells, F.B.; Kirby, M.; Saltini, C.; Crystal, R.G. Activation of alveolar macrophages in asymptomatic HIV-infected individuals. J. Immunol. 1993, 150, 1019–1028. [Google Scholar]
- White, D.A.; Gellene, R.A.; Gupta, S.; Cunningham-Rundles, C.; Stover, D.E. Pulmonary cell populations in the immunosuppressed patient. Bronchoalveolar lavage findings during episodes of pneumonitis. Chest 1985, 88, 352–359. [Google Scholar] [CrossRef] [PubMed]
- Wallace, J.M.; Barbers, R.G.; Oishi, J.S.; Prince, H. Cellular and T-lymphocyte subpopulation profiles in bronchoalveolar lavage fluid from patients with acquired immunodeficiency syndrome and pneumonitis. Am. Rev. Respir. Dis. 1984, 130, 786–790. [Google Scholar] [PubMed]
- Freire, M.O.; van Dyke, T.E. Natural resolution of inflammation. Periodontol. 2000 2013, 63, 149–164. [Google Scholar] [CrossRef] [PubMed]
- Bruggeman, L.A.; Dikman, S.; Meng, C.; Quaggin, S.E.; Coffman, T.M.; Klotman, P.E. Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J. Clin. Investig. 1997, 100, 84–92. [Google Scholar] [CrossRef]
- Kopp, J.B.; Klotman, M.E.; Adler, S.H.; Bruggeman, L.A.; Dickie, P.; Marinos, N.J.; Eckhaus, M.; Bryant, J.L.; Notkins, A.L.; Klotman, P.E. Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes. Proc. Natl. Acad. Sci. USA 1992, 89, 1577–1581. [Google Scholar] [CrossRef]
- Ray, P.E.; Bruggeman, L.A.; Weeks, B.S.; Kopp, J.B.; Bryant, J.L.; Owens, J.W.; Notkins, A.L.; Klotman, P.E. bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice. Kidney Int. 1994, 46, 759–772. [Google Scholar] [CrossRef]
- Barisoni, L.; Bruggeman, L.A.; Mundel, P.; D’Agati, V.D.; Klotman, P.E. HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy. Kidney Int. 2000, 58, 173–181. [Google Scholar] [CrossRef]
- Jacob, B.A.; Porter, K.M.; Elms, S.C.; Cheng, P.Y.; Jones, D.P.; Sutliff, R.L. HIV-1-induced pulmonary oxidative and nitrosative stress: Exacerbated response to endotoxin administration in HIV-1 transgenic mouse model. Am. J. Physiol. Lung Cell. Mol. Physiol. 2006, 291, L811-9. [Google Scholar] [CrossRef]
- Bruggeman, L.A.; Thomson, M.M.; Nelson, P.J.; Kopp, J.B.; Rappaport, J.; Klotman, P.E.; Klotman, M.E. Patterns of HIV-1 mRNA expression in transgenic mice are tissue-dependent. Virology 1994, 202, 940–948. [Google Scholar] [CrossRef]
- Leonard, J.; Khillan, J.S.; Gendelman, H.E.; Adachi, A.; Lorenzo, S.; Westphal, H.; Martin, M.A.; Meltzer, M.S. The human immunodeficiency virus long terminal repeat is preferentially expressed in Langerhans cells in transgenic mice. Aids Res. Hum. Retrovir. 1989, 5, 421–430. [Google Scholar] [CrossRef]
- Putatunda, R.; Zhang, Y.; Li, F.; Yang, X.F.; Barbe, M.F.; Hu, W. Adult neurogenic deficits in HIV-1 Tg26 transgenic mice. J. Neuroinflamm. 2018, 15, 287. [Google Scholar] [CrossRef]
- Ammosova, T.; Platonov, M.; Ivanov, A.; Kont, Y.S.; Kumari, N.; Kehn-Hall, K.; Jerebtsova, M.; Kulkarni, A.A.; Uren, A.; Kovalskyy, D.; et al. 1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription. Br. J. Pharmacol. 2014, 171, 5059–5075. [Google Scholar] [PubMed]
- Jerebtsova, M.; Wong, E.; Przygodzki, R.; Tang, P.; Ray, P.E. A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice. Am. J. Physiol. Heart Circ. Physiol. 2007, 292, H743-50. [Google Scholar] [CrossRef] [PubMed]
- Heremans, H.; Dillen, C.; Groenen, M.; Matthys, P.; Billiau, A. Role of interferon-gamma and nitric oxide in pulmonary edema and death induced by lipopolysaccharide. Am. J. Respir. Crit. Care Med. 2000, 161, 110–117. [Google Scholar] [CrossRef] [PubMed]
- Brown, L.F.; Detmar, M.; Claffey, K.; Nagy, J.A.; Feng, D.; Dvorak, A.M.; Dvorak, H.F. Vascular permeability factor/vascular endothelial growth factor: A multifunctional angiogenic cytokine. Exs 1997, 79, 233–269. [Google Scholar] [PubMed]
- Bakakos, P.; Patentalakis, G.; Papi, A. Vascular Biomarkers in Asthma and COPD. Curr. Top. Med. Chem. 2016, 16, 1599–1609. [Google Scholar] [CrossRef] [PubMed]
- Kwon, J.; Wang, A.; Burke, D.J.; Boudreau, H.E.; Lekstrom, K.J.; Korzeniowska, A.; Sugamata, R.; Kim, Y.S.; Yi, L.; Ersoy, I.; et al. Peroxiredoxin 6 (Prdx6) supports NADPH oxidase1 (Nox1)-based superoxide generation and cell migration. Free Radic. Biol. Med. 2016, 96, 99–115. [Google Scholar] [CrossRef]
- Mattison, P.C.; Soler-Garcia, A.A.; Das, J.R.; Jerebtsova, M.; Perazzo, S.; Tang, P.; Ray, P.E. Role of circulating fibroblast growth factor-2 in lipopolysaccharide-induced acute kidney injury in mice. Pediatric Nephrol. 2012, 27, 469–483. [Google Scholar] [CrossRef]
- Lin, X.; Kumari, N.; DeMarino, C.; Kont, Y.S.; Ammosova, T.; Kulkarni, A.; Jerebtsova, M.; Vazquez-Meves, G.; Ivanov, A.; Dmytro, K.; et al. Inhibition of HIV-1 infection in humanized mice and metabolic stability of protein phosphatase-1-targeting small molecule 1E7-03. Oncotarget 2017, 8, 76749–76769. [Google Scholar] [CrossRef]
- Verollet, C.; Souriant, S.; Bonnaud, E.; Jolicoeur, P.; Raynaud-Messina, B.; Kinnaer, C.; Fourquaux, I.; Imle, A.; Benichou, S.; Fackler, O.T.; et al. HIV-1 reprograms the migration of macrophages. Blood 2015, 125, 1611–1622. [Google Scholar] [CrossRef]
- Morris, A.; Crothers, K.; Beck, J.M.; Huang, L.; American Thoracic Society Committee on H.I.V.P.D. An official ATS workshop report: Emerging issues and current controversies in HIV-associated pulmonary diseases. Proc. Am. Thorac. Soc. 2011, 8, 17–26. [Google Scholar] [CrossRef] [PubMed]
- Esser, R.; von Briesen, H.; Brugger, M.; Ceska, M.; Glienke, W.; Muller, S.; Rehm, A.; Rubsamen-Waigmann, H.; Andreesen, R. Secretory repertoire of HIV-infected human monocytes/macrophages. Pathobiol.: J. Immunopathol. Mol. Cell. Biol. 1991, 59, 219–222. [Google Scholar] [CrossRef] [PubMed]
- Cobos-Jimenez, V.; Booiman, T.; Hamann, J.; Kootstra, N.A. Macrophages and HIV-1. Curr. Opin. Hiv Aids 2011, 6, 385–390. [Google Scholar] [CrossRef]
- Verani, A.; Sironi, F.; Siccardi, A.G.; Lusso, P.; Vercelli, D. Inhibition of CXCR4-tropic HIV-1 infection by lipopolysaccharide: Evidence of different mechanisms in macrophages and T lymphocytes. J. Immunol. 2002, 168, 6388–6395. [Google Scholar] [CrossRef]
- Simard, S.; Maurais, E.; Gilbert, C.; Tremblay, M.J. LPS reduces HIV-1 replication in primary human macrophages partly through an endogenous production of type I interferons. Clin. Immunol. 2008, 127, 198–205. [Google Scholar] [CrossRef]
- Maus, U.A.; Koay, M.A.; Delbeck, T.; Mack, M.; Ermert, M.; Ermert, L.; Blackwell, T.S.; Christman, J.W.; Schlondorff, D.; Seeger, W.; et al. Role of resident alveolar macrophages in leukocyte traffic into the alveolar air space of intact mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 2002, 282, L1245-52. [Google Scholar] [CrossRef]
- Borregaard, N. Neutrophils, from marrow to microbes. Immunity 2010, 33, 657–670. [Google Scholar] [CrossRef]
- Nathan, C. Neutrophils and immunity: Challenges and opportunities. Nat. Rev. Immunol. 2006, 6, 173–182. [Google Scholar] [CrossRef]
- Bergamini, A.; Faggioli, E.; Bolacchi, F.; Gessani, S.; Cappannoli, L.; Uccella, I.; Demin, F.; Capozzi, M.; Cicconi, R.; Placido, R.; et al. Enhanced production of tumor necrosis factor-alpha and interleukin-6 due to prolonged response to lipopolysaccharide in human macrophages infected in vitro with human immunodeficiency virus type 1. J. Infect. Dis. 1999, 179, 832–842. [Google Scholar] [CrossRef][Green Version]
- Bierhaus, A.; Chen, J.; Liliensiek, B.; Nawroth, P.P. LPS and cytokine-activated endothelium. Semin. Thromb. Hemost. 2000, 26, 571–587. [Google Scholar] [CrossRef]
Parameter | Score Per Field | |||
---|---|---|---|---|
0 | 1 | 2 | ||
I. | Neutrophils in the alveolar space | 0 | 1–5 | >5 |
II. | Neutrophils in the interstitial space | 0 | 1–5 | >5 |
III. | Hyaline membranes | 0 | 1 | >1 |
IV. | Proteinaceous debris filling air spaces | 0 | 1 | >1 |
V. | Alveolar septal thickening | 0 | 2x–4x | >4x |
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Jerebtsova, M.; Ahmad, A.; Niu, X.; Rutagarama, O.; Nekhai, S. HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice. Viruses 2020, 12, 204. https://doi.org/10.3390/v12020204
Jerebtsova M, Ahmad A, Niu X, Rutagarama O, Nekhai S. HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice. Viruses. 2020; 12(2):204. https://doi.org/10.3390/v12020204
Chicago/Turabian StyleJerebtsova, Marina, Asrar Ahmad, Xiaomei Niu, Ornela Rutagarama, and Sergei Nekhai. 2020. "HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice" Viruses 12, no. 2: 204. https://doi.org/10.3390/v12020204
APA StyleJerebtsova, M., Ahmad, A., Niu, X., Rutagarama, O., & Nekhai, S. (2020). HIV-1 Transcription Inhibitor 1E7-03 Restores LPS-Induced Alteration of Lung Leukocytes’ Infiltration Dynamics and Resolves Inflammation in HIV Transgenic Mice. Viruses, 12(2), 204. https://doi.org/10.3390/v12020204