Abstract
Alveolar macrophages (AMs) can initiate lung inflammation by producing pro-inflammatory cytokines and chemokines, but they participate actively in the prevention of inflammation during acute lung injury (ALI). Heme oxygenase-1 (HO-1) is mainly expressed in AMs and has anti-inflammatory properties in ALI, but the anti-inflammatory mechanisms of HO-1 are largely unknown. In this study, AMs were treated with saline, LPS (1 μg/ml), hemin (10 μM), zinc protoporphyrin (ZnPP; 10 μM, 1 h prior to LPS and hemin), SB203580 (10 μM, 1 h prior to LPS and hemin), or their combination up to 24 h. The specific HO-1 inhibitor ZnPP and SB203580 were used to inhibit the effects of HO-1 and the phosphorylated p38 mitogen-activated protein kinase (MAPK), respectively. The protein levels of HO-1 and p38 MAPK were analyzed by western blotting; arginase activity was measured in lysates obtained from cultured cells; nitric oxide production in the extracellular medium of AMs cultured for 24 h was monitored by assessing nitrite levels; the phagocytic ability of macrophage was measured by neutral red uptake. IL-10 of culture supernatants in AMs was determined by enzyme-linked immunosorbent assay. The results indicated that HO-1 induced by hemin increased arginase activity and phagocytic ability and decreased iNOS activity via p38 MAPK pathway in primary rat AMs. These changes and p38 MAPK may be the anti-inflammatory mechanism of HO-1 induced by hemin in primary rat AMs.
Similar content being viewed by others
References
Zhao, M., L.G. Fernandez, A. Doctor, A.K. Sharma, A. Zarbock, and C.G. Tribble. 2006. Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury. American Journal of Physiology. Lung Cellular and Molecular Physiology 291: L1018–L1026.
Matute, B.G., and T.R. Martin. 2003. Science review: apoptosis in acute lung injury. Critical Care 7: 355–358.
Miyake, Y., H. Kaise, K. Isono, H. Koseki, K. Kohno, and M. Tanaka. 2007. Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II cells. Journal of Immunology 178: 5001–5009.
Pang, Q.F., Q.M. Zhou, S. Zeng, L.D. Dou, J. Yong, and Y.M. Zeng. 2008. Protective effect of heme oxygenase-1 on lung injury induced by erythrocyte instillation in rats. Chinese Medical Journal 121: 1688–1692.
Deshane, J., M. Wright, and A. Agarwal. 2005. Heme oxygenase-1 expression in disease states. Acta Biochimica 52: 273–284.
Kirkby, K.A., and C.A. Adin. 2006. Products of heme oxygenase and their potential therapeutic applications. American Journal of Physiology. Renal Physiology 290: F563–F571.
Takaki, S., N. Takeyama, Y. Kajita, T. Yabuki, H. Noguchi, and Y. Miki. 2010. Beneficial effects of the heme oxygenase-1/carbon monoxide system in patients with severe sepsis/septic shock. Intensive Care Medicine 36: 42–48.
Morse, D., L. Lin, A.M. Choi, and S.W. Ryter. 2009. Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease. Free Radical Biology & Medicine 47: 1–12.
McCourtie, A.S., H.E. Merry, A.S. Farivar, C.H. Goss, and M.S. Mulligan. 2008. Alveolar macrophage secretory products augment the response of rat pulmonary artery endothelial cells to hypoxia and reoxygenation. The Annals of Thoracic Surgery 85: 1056–1060.
Meyer, M., F. Huaux, X. Gavilanes, S. van den Brûle, P. Lebecque, S. Lo Re, and D. Lison. 2009. Azithromycin reduces exaggerated cytokine production by M1 alveolar macrophages in cystic fibrosis. American Journal of Respiratory Cell and Molecular Biology 41: 590–602.
Chen, W., W. Zhang, W. Shen, and K. Wang. 2010. Effects of the acid polysaccharide fraction isolated from a cultivated Cordyceps sinensis on macrophages in vitro. Cellular Immunology 262: 69–74.
Otterbein, L.E., and A.M. Choi. 2000. Heme oxygenase: colors of defense against cellular stress. American Journal of Physiology 270: L1029–L1037.
Otterbein, L.E., M.P. Soares, K. Yamashita, and F.H. Bach. 2003. Heme oxygenase-1: unleashing the protective properties of heme. Trends in Immunology 24: 449–455.
Kim, H.P., S.W. Ryter, and A.M. Choi. 2006. Co as a cellular signaling molecule. Annual Review of Pharmacology and Toxicology 46: 411–449.
Carraway, M.S., A.J. Ghio, J.D. Carter, and C.A. Piantadosi. 2000. Expression of heme oxygenase-1 in the lung in chronic hypoxia. American Journal of Respiratory Cell and Molecular Biology 278: L806–L812.
Carraway, M.S., A.J. Ghio, J.L. Taylor, and C.A. Piantadosi. 1998. Induction of ferritin and heme oxygenase-1 by endotoxin in the lung. American Journal of Lung Cellular and Molecular Physiology 275: L583–L592.
Eyssen-Hernandez, R., A. Ladoux, and C. Frelin. 1996. Differential regulation of cardiac heme oxygenase-1 and vascular endothelial growth factor mRNA expressions by hemin, heavy metals, heat shock and anoxia. FEBS Letters 382: 229–233.
Ferrándiz, M.L., and I. Devesa. 2008. Inducers of heme oxygenase-1. Current Pharmaceutical Design 14: 473–486.
Ashino, T., R. Yamanaka, M. Yamamoto, H. Shimokawa, K. Sekikawa, and Y. Iwakura. 2008. Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages. Molecular Immunology 45: 2106–2115.
Lin, H.Y., S.H. Juan, S.C. Shen, F.L. Hsu, and Y.C. Chen. 2003. Inhibition of lipopolysaccharide induced nitric oxide production by flavonoids in RAW264.7 macrophages involves heme oxygenase-1. Biochemical Pharmacology 66: 1821–1832.
Lin, H.Y., S.C. Shen, and Y.C. Chen. 2005. Anti-inflammatory effect of heme oxygenase 1: glycosylation and nitric oxide inhibition in macrophages. Journal of Cellular Physiology 202: 579–590.
Maestrelli, P., C. Páska, M. Saetta, G. Turato, Y. Nowicki, and S. Monti. 2003. Decreased haem oxygenase-1 and increased inducible nitric oxide synthase in the lung of severe COPD patients. European Respiratory Journal 21: 971–976.
Wang, W.W., C.P. Jenkinson, J.M. Griscavage, R.M. Kern, N.S. Arabolos, and R.E. Byrns. 1995. Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide. Biochemical and Biophysical Research Communications 210: 1009–1016.
Meurs, H., H. Maarsingh, and J. Zaagsma. 2003. Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends in Pharmacological Sciences 24: 450–455.
Zhai, Z., A. Solco, L. Wu, E.S. Wurtele, M.L. Kohut, P.A. Murphy, and J.E. Cunnick. 2009. Echinacea increases arginase activity and has anti-inflammatory properties in RAW 264.7 macrophage cells, indicative of alternative macrophage activation. Journal of Ethnopharmacology 122: 76–85.
Mantovani, A., S. Sozzani, M. Locati, P. Allavena, and A. Sica. 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology 23: 549–555.
Gratchev, A., J. Kzhyshkowska, J. Utikal, and S. Goerdt. 2005. Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Scandinavian Journal of Immunology 61: 10–17.
Lee, J.C., J.T. Laydon, and P.C. McDonnell. 1994. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739–746.
Han, J., J.D. Lee, L. Bibbs, and R.J. Ulevitch. 1994. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808–811.
Yong, H.Y., M.S. Koh, and A. Moon. 2009. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opinion Investigation 18: 1893–1905.
Chanteux, H., A.C. Guisset, C. Pilette, and Y. Sibille. 2002. LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms. Respiratory Research 8: 71.
Schwacha, M.G., I.H. Chaudey, and M. Alexander. 2003. Regulation of macrophage IL-10 production postinjury via beta2 integrin signaling and the P38 MAP kinase pathway. Shock 20: 529–535.
Seimon, T.A., Y. Wang, S. Han, and T. Senokuchi. 2009. Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice. The Journal of Clinical Investigation 119: 886–898.
Li, Y.Z., Y.X. Zhong, X. Fang, and C.C. Bang. 2008. Effect of radix paeoniae rubra on expression of p38 MAPK/iNOS/HO-1 in rats with lipopolysaccharide-induced acute lung injury. Chinese Medical Journal 121: 1688–1692.
Wang, X.M., H.P. Kim, K. Nakahira, S.W. Ryter, and A.M. Choi. 2009. The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1. Journal of Immunology 182: 3809–3818.
Williams, J.A., C.H. Pontzer, and E. Shacter. 2000. Regulation of macrophage interleukin-6 (IL-6) and IL-10 expression by prostaglandin E2: the role of p38 mitogen-activated protein kinase. Journal of Interferon and Cytokine Research 20: 291–298.
Ricchetti, G.A., L.M. Williams, and B.M. Foxwell. 2004. Heme oxygenase 1 expression induced by IL-10 requires STAT-3 and phosphoinositol-3 kinase and is inhibited by lipopolysaccharide. Journal of Leukocyte Biology 76: 719–726.
Lee, T.S., and L.Y. Chau. 2002. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nature Medicine 8: 240–246.
Acknowledgments
This work was supported by the following grant the Priority Academic Program Development of Jiangsu Higher Education Institutions, Peak of the six personnel in Jiangsu Province, and Jiangsu Province Graduate Education Innovation project no. CX09S_035Z and Xuzhou Medical College president’s fund (no. 09KJZ07).
Conflict of Interest
All of the authors declared that there was not any actual or potential conflict of interest in this paper.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hualin, C., Wenli, X., Dapeng, L. et al. The Anti-inflammatory Mechanism of Heme Oxygenase-1 Induced by Hemin in Primary Rat Alveolar Macrophages. Inflammation 35, 1087–1093 (2012). https://doi.org/10.1007/s10753-011-9415-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10753-011-9415-4