Macrophage diversity in renal injury and repair

Journal of Clinical Investigation

Volumn 118, Issue 11, 2008, Pages 3522-3530

  Ricardo, Sharon D ^a   Van Goor, Harry ^b   Eddy, Allison A ^c  

^a MONASH UNIVERSITY   (Australia)

^b UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^c UNIVERSITY OF WASHINGTON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL FUNCTION; CELL RENEWAL; HOST RESISTANCE; HUMAN; IMMUNE RESPONSE; KIDNEY ALLOGRAFT; KIDNEY CELL; KIDNEY INJURY; MACROPHAGE; MACROPHAGE MIGRATION; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; REVIEW; TISSUE REPAIR;

ANIMALS; HUMANS; KIDNEY; KIDNEY DISEASES; MACROPHAGE ACTIVATION; MACROPHAGES; MODELS, BIOLOGICAL; REGENERATION;

EID: 55849103960     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI36150     Document Type: Review

References (125)

1. Pistole, T.G., and Britko, J.L. 1978. Bactericidal activity of amebocytes from the horseshoe crab, Limulus polyphemus. J. Invertebr. Pathol. 31:376-382.
2. Takahashi, K., and Naito, M. 1993. Development, differentiation, and proliferation of macrophages in the rat yolk sac. Tissue Cell. 25:351-362.
3. Takahashi, K., Yamamura, F., and Naito, M. 1989. Differentiation, maturation, and proliferation of macrophages in the mouse yolk sac: a light-microscopic, enzyme-cytochemical, immunohistochemical, and ultrastructural study. J. Leukoc. Biol. 45:87-96.
4. Morioka, Y., Naito, M., Sato, T., and Takahashi, K. 1994. Immunophenotypic and ultrastructural heterogeneity of macrophage differentiation in bone marrow and fetal hematopoiesis of mouse in vitro and in vivo. J. Leukoc. Biol. 55:642-651.
5. Hume, D.A. 2006. The mononuclear phagocyte system. Curr. Opin. Immunol. 18:49-53.
6. Lichanska, A.M., et al. 1999. Differentiation of the mononuclear phagocyte system during mouse embryogenesis: the role of transcription factor PU.1. Blood. 94:127-138.
7. Shepard, J.L., and Zon, L.I. 2000. Developmental derivation of embryonic and adult macrophages. Curr. Opin. Hematol. 7:3-8.
8. Hume, D.A., et al. 2002. The mononuclear phagocyte system revisited. J. Leukoc. Biol. 72:621-627.
9. Henson, P.M., and Hume, D.A. 2006. Apoptotic cell removal in development and tissue homeostasis. Trends Immunol. 27:244-250.
10. Rae, F., et al. 2007. Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter. Dev. Biol. 308:232-246.
11. Lichanska, A.M., and Hume, D.A. 2000. Origins and functions of phagocytes in the embryo. Exp. Hematol. 28:601-611.
12. Gordon, S., and Taylor, P.R. 2005. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5:953-964.
13. Rivollier, A., et al. 2004. Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment. Blood. 104:4029-4037.
14. Boyle, W.J., Simonet, W.S., and Lacey, D.L. 2003. Osteoclast differentiation and activation. Nature. 423:337-342.
15. Geissmann, F., Jung, S., and Littman, D.R. 2003. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 19:71-82.
16. Sunderkotter, C., et al. 2004. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 172:4410-4417.
17. Fogg, D.K., et al. 2006. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science. 311:83-87.
18. Martinez, F.O., Sica, A., Mantovani, A., and Locati, M. 2008. Macrophage activation and polarization. Front. Biosci. 13:453-461.
19. Mantovani, A., et al. 2004. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25:677-686.
20. Chen, Y., and Wood, K.J. 2007. Interleukin-23 and TH17 cells in transplantation immunity: does 23+17 equal rejection? Transplantation. 84:1071-1074.
21. Ma, H.L., et al. 2008. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J. Clin. Invest. 118:597-607.
22. Krueger, G.G., et al. 2007. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356:580-592.
23. Mantovani, A., Sica, A., and Locati, M. 2007. New vistas on macrophage differentiation and activation. Eur. J. Immunol. 37:14-16.
24. Mantovani, A., Sica, A., and Locati, M. 2005. Macrophage polarization comes of age. Immunity. 23:344-346.
25. Gordon, S. 2003. Alternative activation of macrophages. Nat. Rev. Immunol. 3:23-35.
26. Kluth, D.C. 2007. Pro-resolution properties of macrophages in renal injury. Kidney Int. 72:234-236.
27. Timmer, A.M., and Nizet, V. 2008. IKKbeta/ NF-kappaB and the miscreant macrophage. J. Exp. Med. 205:1255-1259.
28. Wang, Y., et al. 2007. Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int. 72:290-299.
29. Mosser, D.M. 2003. The many faces of macrophage activation. J. Leukoc. Biol. 73:209-212.
30. Wilson, H.M., Walbaum, D., and Rees, A.J. 2004. Macrophages and the kidney. Curr. Opin. Nephrol. Hypertens. 13:285-290.
31. Bourlier, V., et al. 2008. Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation. 117:806-815.
32. Duffield, J.S. 2003. The inflammatory macrophage: a story of Jekyll and Hyde. Clin. Sci. (Lond.) 104:27-38.
33. Mantovani, A., Sozzani, S., Locati, M., Allavena, P., and Sica, A. 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23:549-555.
34. Watkins, S.K., Egilmez, N.K., Suttles, J., and Stout, R.D. 2007. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J. Immunol. 178:1357-1362.
35. Sica, A., and Bronte, V. 2007. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 117:1155-1166.
36. Tsuda, Y., et al. 2004. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity. 21:215-226.
37. Jo, S.K., Sung, S.A., Cho, W.Y., Go, K.J., and Kim, H.K. 2006. Macrophages contribute to the initiation of ischaemic acute renal failure in rats. Nephrol. Dial. Transplant. 21:1231-1239.
38. Day, Y.J., Huang, L., Ye, H., Linden, J., and Okusa, M.D. 2005. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am. J. Physiol. Renal Physiol. 288:F722-F731.
39. Ko, G.J., Boo, C.S., Jo, S.K., Cho, W.Y., and Kim, H.K. 2008. Macrophages contribute to the development of renal fibrosis following ischaemia/ reperfusion-induced acute kidney injury. Nephrol. Dial. Transplant. 23:842-852.
40. Diamond, J.R., and Pesek-Diamond, I. 1991. Sublethal X-irradiation during acute puromycin nephrosis prevents late renal injury: role of macrophages. Am. J. Physiol. 260:F779-F786.
41. van Goor, H., van der Horst, M.L., Fidler, V., and Grond, J. 1992. Glomerular macrophage modulation affects mesangial expansion in the rat after renal ablation. Lab. Invest. 66:564-571.
42. Duffield, J.S., et al. 2005. Conditional ablation of macrophages halts progression of crescentic glomerulonephritis. Am. J. Pathol. 167:1207-1219.
43. Friedman, S.L. 2005. Mac the knife? Macrophages-the double-edged sword of hepatic fibrosis. J. Clin. Invest. 115:29-32.
44. Chazaud, B., et al. 2003. Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth. J. Cell Biol. 163:1133-1143.
45. Arnold, L., et al. 2007. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204:1057-1069.
46. Pull, S.L., Doherty, J.M., Mills, J.C., Gordon, J.I., and Stappenbeck, T.S. 2005. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl. Acad. Sci. U. S. A. 102:99-104.
47. Ramsay, R.G., et al. 2004. Colony-stimulating factor-1 promotes clonogenic growth of normal murine colonic crypt epithelial cells in vitro. J. Interferon Cytokine Res. 24:416-427.
48. Ide, H., et al. 2002. Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression. Proc. Natl. Acad. Sci. U. S. A. 99:14404-14409.
49. Kacinski, B.M., et al. 1991. FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene. 6:941-952.
50. Herbert, D.R., et al. 2004. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity. 20:623-635.
51. Rauh, M.J., et al. 2005. SHIP represses the generation of alternatively activated macrophages. Immunity. 23:361-374.
52. Kurts, C., Heymann, F., Lukacs-Kornek, V., Boor, P., and Floege, J. 2007. Role of T cells and dendritic cells in glomerular immunopathology. Semin. Immunopathol. 29:317-335.
53. Chadban, S.J., and Atkins, R.C. 2005. Glomerulonephritis. Lancet. 365:1797-1806.
54. Kalluri, R., Danoff, T.M., Okada, H., and Neilson, E.G. 1997. Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice. J. Clin. Invest. 100:2263-2275.
55. Hume, D.A., Robinson, A.P., MacPherson, G.G., and Gordon, S. 1983. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. Relationship between macrophages, Langerhans cells, reticular cells, and dendritic cells in lymphoid and hematopoietic organs. J. Exp. Med. 158:1522-1536.
56. Brown, F.G., et al. 1999. Up-regulation of macrophage migration inhibitory factor in acute renal allograft rejection in the rat. Clin. Exp. Immunol. 118:329-336.
57. Wyburn, K., et al. 2005. Macrophage-derived interleukin-18 in experimental renal allograft rejection. Nephrol. Dial. Transplant. 20:699-706.
58. Tipping, P.G., and Holdsworth, S.R. 2006. T cells in crescentic glomerulonephritis. J. Am. Soc. Nephrol. 17:1253-1263.
59. Border, W.A., and Noble, N.A. 1994. Transforming growth factor beta in tissue fibrosis. N. Engl. J. Med. 331:1286-1292.
60. Eddy, A.A. 2005. Progression in chronic kidney disease. Adv. Chronic Kidney Dis. 12:353-365.
61. Border, W.A. 1994. Transforming growth factor-beta and the pathogenesis of glomerular diseases. Curr. Opin. Nephrol. Hypertens. 3:54-58.
62. Li, J., et al. 2006. Inhibition of p38 mitogen-activated protein kinase and transforming growth factor-beta1/Smad signaling pathways modulates the development of fibrosis in adriamycin-induced nephropathy. Am. J. Pathol. 169:1527-1540.
63. Iwano, M., et al. 2002. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110:341-350.
64. Weitkamp, B., Cullen, P., Plenz, G., Robenek, H., and Rauterberg, J. 1999. Human macrophages synthesize type VIII collagen in vitro and in the atherosclerotic plaque. FASEB J. 13:1445-1457.
65. Tsunawaki, S., Sporn, M., Ding, A., and Nathan, C. 1988. Deactivation of macrophages by transforming growth factor-beta. Nature. 334:260-262.
66. Schnoor, M., et al. 2008. Production of type VI collagen by human macrophages: a new dimension in macrophage functional heterogeneity. J. Immunol. 180:5707-5719.
67. Anders, H.J., et al. 2003. CC chemokine ligand 5/ RANTES chemokine antagonists aggravate glomerulonephritis despite reduction of glomerular leukocyte infiltration. J. Immunol. 170:5658-5666.
68. Yokoo, T., et al. 1999. Prophylaxis of antibody-induced acute glomerulonephritis with genetically modified bone marrow-derived vehicle cells. Hum. Gene Ther. 10:2673-2678.
69. Yang, J., et al. 2003. Targeting of macrophage activity by adenovirus-mediated intragraft overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 ameliorates adenovirus-mediated chronic graft injury, whereas stimulation of macrophages by overexpression of IFN-gamma accelerates chronic graft injury in a rat renal allograft model. J. Am. Soc. Nephrol. 14:214-225.
70. Nishida, M., et al. 2005. Adoptive transfer of macrophages ameliorates renal fibrosis in mice. Biochem. Biophys. Res. Commun. 332:11-16.
71. Nishida, M., et al. 2002. Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis. J. Clin. Invest. 110:1859-1868.
72. Zhang, G., et al. 2003. Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy. J. Am. Soc. Nephrol. 14:1254-1271.
73. Wang, Y., et al. 2007. Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int. 72:290-299.
74. Wilson, H.M., et al. 2005. Inhibition of macrophage nuclear factor-kappaB leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo. Am. J. Pathol. 167:27-37.
75. Wilson, H.M., et al. 2002. Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis. Mol. Ther. 6:710-717.
76. Humphreys, B.D., and Bonventre, J.V. 2007. The contribution of adult stem cells to renal repair. Nephrol. Ther. 3:3-10.
77. Poulsom, R., et al. 2001. Bone marrow contributes to renal parenchymal turnover and regeneration. J. Pathol. 195:229-235.
78. Rookmaaker, M.B., et al. 2003. Bone-marrow-derived cells contribute to glomerular endothelial repair in experimental glomerulonephritis. Am. J. Pathol. 163:553-562.
79. Kale, S., et al. 2003. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J. Clin. Invest. 112:42-49.
80. Lin, F., et al. 2003. Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. J. Am. Soc. Nephrol. 14:1188-1199.
81. Grimm, P.C., et al. 2001. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N. Engl. J. Med. 345:93-97.
82. Nishida, M., et al. 2003. Renal tubular regeneration by bone marrow-derived cells in a girl after bone marrow transplantation. Am. J. Kidney Dis. 42:E10-E12.
83. Gupta, S., Verfaillie, C., Chmielewski, D., Kim, Y., and Rosenberg, M.E. 2002. A role for extrarenal cells in the regeneration following acute renal failure. Kidney Int. 62:1285-1290.
84. Li, J., Deane, J.A., Campanale, N.V., Bertram, J.F., and Ricardo, S.D. 2006. Blockade of p38 mitogen-activated protein kinase and TGF-beta1/Smad signaling pathways rescues bone marrow-derived peritubular capillary endothelial cells in adriamycin-induced nephrosis. J. Am. Soc. Nephrol. 17:2799-2811.
85. Li, J., Deane, J.A., Campanale, N.V., Bertram, J.F., and Ricardo, S.D. 2007. The contribution of bone marrow-derived cells to the development of renal interstitial fibrosis. Stem Cells. 25:697-706.
86. Masuya, M., et al. 2003. Hematopoietic origin of glomerular mesangial cells. Blood. 101:2215-2218.
87. Camargo, F.D., Chambers, S.M., and Goodell, M.A. 2004. Stem cell plasticity: from transdifferentiation to macrophage fusion. Cell Prolif. 37:55-65.
88. Imasawa, T., et al. 2001. The potential of bone marrow-derived cells to differentiate to glomerular mesangial cells. J. Am. Soc. Nephrol. 12:1401-1409.
89. Ito, T., Suzuki, A., Imai, E., Okabe, M., and Hori, M. 2001. Bone marrow is a reservoir of repopulating mesangial cells during glomerular remodeling. J. Am. Soc. Nephrol. 12:2625-2635.
90. Duffield, J.S., et al. 2005. Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J. Clin. Invest. 115:1743-1755.
91. Lin, F., Moran, A., and Igarashi, P. 2005. Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J. Clin. Invest. 115:1756-1764.
92. Li, L., Truong, P., Igarashi, P., and Lin, F. 2007. Renal and bone marrow cells fuse after renal ischemic injury. J. Am. Soc. Nephrol. 18:3067-3077.
93. Held, P.K., et al. 2006. In vivo genetic selection of renal proximal tubules. Mol. Ther. 13:49-58.
94. Willenbring, H., et al. 2004. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat. Med. 10:744-748.
95. Vignery, A. 2000. Osteoclasts and giant cells: macrophage-macrophage fusion mechanism. Int. J. Exp. Pathol. 81:291-304.
96. Bailey, A.S., et al. 2006. Myeloid lineage progenitors give rise to vascular endothelium. Proc. Natl. Acad. Sci. U. S. A. 103:13156-13161.
97. Zhao, Y., Glesne, D., and Huberman, E. 2003. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc. Natl. Acad. Sci. U. S. A. 100:2426-2431.
98. Havemann, K., Pujol, B.F., and Adamkiewicz, J. 2003. In vitro transformation of monocytes and dendritic cells into endothelial like cells. Adv. Exp. Med. Biol. 522:47-57.
99. Mestas, J., and Hughes, C.C. 2004. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172:2731-2738.
100. Bouhlel, M.A., et al. 2007. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6:137-143.
101. Tacke, F., et al. 2007. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117:185-194.
102. Gordon, S. 2007. Macrophage heterogeneity and tissue lipids. J. Clin. Invest. 117:89-93.
103. Kitagawa, K., et al. 2004. Blockade of CCR2 Ameliorates Progressive Fibrosis in Kidney. Am. J. Pathol. 165:237-246.
104. Takase, O., et al. 2003. Gene transfer of truncated IkappaBalpha prevents tubulointerstitial injury. Kidney Int. 63:501-513.
105. Nahrendorf, M., et al. 2007. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204:3037-3047.
106. Furuichi, K., Gao, J.L., and Murphy, P.M. 2006. Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury. Am. J. Pathol. 169:372-387.
107. Ishida, Y., Gao, J.L., and Murphy, P.M. 2008. Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function. J. Immunol. 180:569-579.
108. Wegener's Granulomatosis Etanercept Trial Research Group. 2005. Etanercept plus standard therapy for Wegener's granulomatosis. N. Engl. J. Med. 352:351-361.
109. Liu, Y. 2004. Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action. Am. J. Physiol. Renal Physiol. 287:F7-F16.
110. Gong, R., Rifai, A., Ge, Y., Chen, S., and Dworkin, L.D. 2008. Hepatocyte growth factor suppresses proinflammatory NFkappaB activation through GSK3beta inactivation in renal tubular epithelial cells. J. Biol. Chem. 283:7401-7410.
111. Ophascharoensuk, V., et al. 1999. Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int. 56:571-580.
112. Mori, R., Shaw, T.J., and Martin, P. 2008. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J. Exp. Med. 205:43-51.
113. Schaefer, L., et al. 2005. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J. Clin. Invest. 115:2223-2233.
114. John, R., and Nelson, P.J. 2007. Dendritic cells in the kidney. J. Am. Soc. Nephrol. 18:2628-2635.
115. Zhang, G., et al. 2003. Urokinase receptor modulates cellular and angiogenic responses in obstructive uropathy. J. Am. Soc. Nephrol. 14:1254-1271.
116. Martinez, F.O., Gordon, S., Locati, M., and Mantovani, A. 2006. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177:7303-7311.
117. Vesey, D.A., et al. 2002. Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production. Kidney Int. 62:31-40.
118. Fallowfield, J.A., et al. 2007. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178:5288-5295.
119. Bronte, V., and Zanovello, P. 2005. Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5:641-654.
120. Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R.K., and Kitani, A. 2006. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat. Med. 12:99-106.
121. Sandovici, M., et al. 2008. Systemic gene therapy with interleukin-13 attenuates renal ischemia-reperfusion injury. Kidney Int. 73:1364-1373.
122. Marriott, H.M., et al. 2005. Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. J. Clin. Invest. 115:359-368.
123. Steinberg, B.E., and Grinstein, S. 2008. Pathogen destruction versus intracellular survival: the role of lipids as phagosomal fate determinants. J. Clin. Invest. 118:2002-2011.
124. Flores-Villanueva, P.O., et al. 2005. A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis. J. Exp. Med. 202:1649-1658.
125. Kim, H.L., et al. 2002. The polymorphism of monocyte chemoattractant protein-1 is associated with the renal disease of SLE. Am. J. Kidney Dis. 40:1146-1152.