Gadolinium chloride (GdCl3), a Kupffer cells inhibitor, attenuates acute lung injury; however, the mechanisms behind this effect are not completely elucidated. We tested the hypothesis that GdCl3 acts through the inhibition of lung parenchymal cellular apoptosis. Two groups of rats were injected intraperitoneally with saline or E. coli lipopolysaccharide. In two additional groups, rats were injected with GdCl3 24？hrs prior to saline or LPS administration. At 12？hrs, lung injury, inflammation, and apoptosis were studied. Lung water content, myeloperoxidase activity, pulmonary apoptosis and mRNA levels of interleukin-1β, -2, -5, -6, -10 and TNF-α rose significantly in LPS-injected animals. Pretreatment with GdCl3 significantly reduced LPS-induced elevation of pulmonary water content, myeloperoxidase activity, cleaved caspase-3 intensity, and attenuated pulmonary TUNEL-positive cells. GdCl3 pre-treatment upregulated IL-1β, -2 and -10 pulmonary gene expression without significantly affecting the others. These results suggest that GdCl3 attenuates acute lung injury through its effects on pulmonary parenchymal apoptosis. 1. Introduction Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a frequent complication of sepsis affecting approximately from 25 to 40% of septic patients and carries a mortality of 40% [1]. Pathogenesis of sepsis-induced ALI proceeds through an early phase characterized by granulocyte migration inside capillaries and monocyte extravasation, an intermediate phase of monocyte differentiation into macrophages (M？s) inside alveoli, and a late phase of diffuse infiltration of alveoli by newly differentiated macrophages and extravasated neutrophils [2]. Recent studies have revealed that ALI is associated with enhanced apoptosis of pulmonary cells, including alveolar and airway epithelial cells as well as endothelial cells [3–5]. Inflammatory cell apoptosis is also enhanced in human with ARDS and in animal models of ALI [6]. The consequence of increased apoptosis in the lungs of septic patients is highly dependent on location of cellular apoptosis. While enhanced apoptosis of neutrophils and removal of apoptotic neutrophils by M？s can attenuate the extent of tissue injury induced by neutrophils, lymphocyte apoptosis is detrimental to the septic host [7]. Likewise, exaggerated apoptosis of pulmonary epithelial and endothelial cells is harmful and leads to a worsening of gas exchange abnormalities. Yet despite the increasing importance of pulmonary apoptosis as a major contributor to the pathogenesis of ALI, factors that
References
[1]
L. B. Ware and M. A. Matthay, “The acute respiratory distress syndrome,” New England Journal of Medicine, vol. 342, no. 18, pp. 1334–1349, 2000.
[2]
D. L. Laskin and J. D. Laskin, “Macrophages, inflammatory mediators, and lung injury,” Methods, vol. 10, no. 1, pp. 61–70, 1996.
[3]
M. Fujita, K. Kuwano, R. Kunitake et al., “Endothelial cell apoptosis in lipopolysaccharide-induced lung injury in mice,” International Archives of Allergy and Immunology, vol. 117, no. 3, pp. 202–208, 1998.
[4]
M. Kawasaki, K. Kuwano, N. Hagimoto et al., “Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor,” American Journal of Pathology, vol. 157, no. 2, pp. 597–603, 2000.
[5]
Y. Kitamura, S. Hashimoto, N. Mizuta et al., “Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice,” American Journal of Respiratory and Critical Care Medicine, vol. 163, no. 3, pp. 762–769, 2001.
[6]
T. R. Martin, M. Nakamura, and G. Matute-Bello, “The role of apoptosis in acute lung injury,” Critical Care Medicine, vol. 31, no. 4, pp. S184–S188, 2003.
[7]
J. J. Hoogerwerf, M. A. van Zoelen, W. J. Wiersinga et al., “Gene expression profiling of apoptosis regulators in patients with sepsis,” Journal of Innate Immunity, vol. 2, no. 5, pp. 461–468, 2010.
[8]
L. Domenic-Lombardo, C. Adembri, M. Consalvo et al., “Evolution of endotoxin induced acute lung injury in the rat,” International Journal of Experimental Pathology, vol. 76, no. 5, pp. 381–390, 1995.
[9]
Y. Fujii, P. Goldberg, and S. N. A. Hussain, “Contribution of macrophages to pulmonary nitric oxide production in septic shock,” American Journal of Respiratory and Critical Care Medicine, vol. 157, no. 5, pp. 1645–1651, 1998.
[10]
J. G. Gaca, D. Palestrant, D. J. Lukes, M. Olausson, W. Parker, and R. D. Davis Jr., “Prevention of acute lung injury in swine: depletion of pulmonary intravascular macrophages using liposomal clodronate,” Journal of Surgical Research, vol. 112, no. 1, pp. 19–25, 2003.
[11]
S. Fujita, S. Arii, K. Monden et al., “Participation of hepatic macrophages and plasma factors in endotoxin- induced liver injury,” Journal of Surgical Research, vol. 59, no. 2, pp. 263–270, 1995.
[12]
H. Kono, H. Fujii, H. Amemiya et al., “Role of Kupffer cells in lung injury in rats administered endotoxin1,” Journal of Surgical Research, vol. 129, no. 2, pp. 176–189, 2005.
[13]
H. Kono, H. Fujii, M. Matsuda, M. Yamamoto, and Y. Matsumoto, “Gadolinium chloride prevents mortality in hepatectomized rats given endotoxin,” Journal of Surgical Research, vol. 96, no. 2, pp. 204–210, 2001.
[14]
C. A. Rivera, B. U. Bradford, K. J. Hunt et al., “Attenuation of CCl4-induced hepatic fibrosis by GdCl3 treatment or dietary glycine,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 281, no. 1, pp. G200–G207, 2001.
[15]
J. Marcinkiewicz, A. Grabowska, J. Bereta, K. Bryniarski, and B. Nowak, “Taurine chloramine down-regulates the generation of murine neutrophil inflammatory mediators,” Immunopharmacology, vol. 40, no. 1, pp. 27–38, 1998.
[16]
T. J. Standiford, R. M. Strieter, N. W. Lukacs, and S. L. Kunkel, “Neutralization of IL-10 increases lethality in endotoxemia: cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor,” Journal of Immunology, vol. 155, no. 4, pp. 2222–2229, 1995.
[17]
L. R. Leon, W. Kozak, K. Rudolph, and M. J. Kluger, “An antipyretic role for interleukin-10 in LPS fever in mice,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 276, no. 1, pp. R81–R89, 1999.
[18]
R. P. Jankov, X. Luo, R. Belcastro et al., “Gadolinium chloride inhibits pulmonary macrophage influx and prevents O2-induced pulmonary hypertension in the neonatal rat,” Pediatric Research, vol. 50, no. 2, pp. 172–183, 2001.
[19]
K. J. Pendino, T. M. Meidhof, D. E. Heck, J. D. Laskin, and D. L. Laskin, “Inhibition of macrophages with gadolinium chloride abrogates ozone-induced pulmonary injury and inflammatory mediator production,” American Journal of Respiratory Cell and Molecular Biology, vol. 13, no. 2, pp. 125–132, 1995.
[20]
K. Sato, M. B. Kadiiska, A. J. Ghio et al., “In vivo lipid-derived free radical formation by NADPH oxidase in acute lung injury induced by lipopolysaccharide: a model for ARDS,” The FASEB Journal, vol. 16, no. 13, pp. 1713–1720, 2002.
[21]
C. R. Roland, B. Naziruddin, T. Mohanakumar, and M. W. Flye, “Gadolinium chloride inhibits Kupffer cell nitric oxide synthase (iNOS) induction,” Journal of Leukocyte Biology, vol. 60, no. 4, pp. 487–492, 1996.
[22]
S. L. Michael, N. R. Pumford, P. R. Mayeux, M. R. Niesman, and J. A. Hinson, “Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species,” Hepatology, vol. 30, no. 1, pp. 186–195, 1999.
[23]
S. S. Du, M. Qiang, Z. C. Zeng et al., “Inactivation of kupffer cells by gadolinium chloride protects murine liver from radiationinduced apoptosis,” International Journal of Radiation Oncology Biology Physics, vol. 76, no. 4, pp. 1225–1234, 2010.
[24]
E. Hamada, T. Nishida, Y. Uchiyama et al., “Activation of Kupffer cells and caspase-3 involved in rat hepatocyte apoptosis induced by endotoxin,” Journal of Hepatology, vol. 30, no. 5, pp. 807–818, 1999.
[25]
Y. Iimuro, M. Yamamoto, H. Kohno, J. Itakura, H. Fujii, and Y. Matsumoto, “Blockade of liver macrophages by gadolinium chloride reduces lethality in endotoxemic rats—analysis of mechanisms of lethality in endotoxemia,” Journal of Leukocyte Biology, vol. 55, no. 6, pp. 723–728, 1994.
[26]
T. Traeger, M. Mikulcak, C. Eipel et al., “Kupffer cell depletion reduces hepatic inflammation and apoptosis but decreases survival in abdominal sepsis,” European Journal of Gastroenterology and Hepatology, vol. 22, no. 9, pp. 1039–1049, 2010.
[27]
G. M. Wray, C. G. Millar, C. J. Hinds, and C. Thiemermann, “Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory faolure, but not the organ injury/dysfunction, caosed by endotoxin,” Shock, vol. 9, no. 5, pp. 329–335, 1998.
[28]
C. M. Lee, G. C. Yeoh, and J. K. Olynyk, “Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 3, pp. 481–488, 2004.
[29]
M. Shakibaei, G. Schulze-Tanzil, Y. Takada, and B. B. Aggarwal, “Redox regulation of apoptosis by members of the TNF superfamily,” Antioxidants and Redox Signaling, vol. 7, no. 3-4, pp. 482–496, 2005.
[30]
H. Okutan, C. Savas, I. F. Ozguner, Z. Yonden, V. C. Eren, and N. Delibas, “Lung injury after aortic occlusion-reperfusion in rats: the role of gadolinium chloride,” Tohoku Journal of Experimental Medicine, vol. 203, no. 4, pp. 267–273, 2004.
[31]
B. Singh, J. W. Pearce, L. N. Gamage, K. Janardhan, and S. Caldwell, “Depletion of pulmonary intravascular macrophages inhibits acute lung inflammation,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 286, no. 2, pp. L363–L372, 2004.
[32]
A. Haimovitz-Friedman, C. Cordon-Cardo, S. Bayoumy et al., “Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation,” Journal of Experimental Medicine, vol. 186, no. 11, pp. 1831–1841, 1997.
[33]
P. A. Kiener, P. M. Davis, B. M. Rankin et al., “Human monocytic cells contain high levels of intracellular fas ligand: rapid release following cellular activation,” Journal of Immunology, vol. 159, no. 4, pp. 1594–1598, 1997.
[34]
R. Bingisser, C. Stey, M. Weller, P. Groscurth, E. Russi, and K. Frei, “Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines,” American Journal of Respiratory Cell and Molecular Biology, vol. 15, no. 1, pp. 64–70, 1996.
[35]
K. L. Serrao, J. D. Fortenberry, M. L. Owens, F. L. Harris, and L. A. S. Brown, “Neutrophils induce apoptosis of lung epithelial cells via release of soluble Fas ligand,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 280, no. 2, pp. L298–L305, 2001.
[36]
B. Brüne, A. von Knethen, and K. B. Sandau, “Nitric oxide and its role in apoptosis,” European Journal of Pharmacology, vol. 351, no. 3, pp. 261–272, 1998.
[37]
K. Heerimeier, R. Schneider, A. Heinloth, C. Wanner, S. Dimmeler, and J. Galle, “Oxidative stress mediates apoptosis induced by oxidized low-density lipoprotein and oxidized lipoprotein(a),” Kidney International, vol. 56, no. 4, pp. 1310–1312, 1999.
[38]
T. Matsumura, A. Ito, T. Takii, H. Hayashi, and K. Onozaki, “Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytes,” Journal of Interferon and Cytokine Research, vol. 20, no. 10, pp. 915–921, 2000.
[39]
C. K. Joseph, S. D. Wright, W. G. Bornmann et al., “Bacterial lipopolysaccharide has structural similarity to ceramide and stimulates ceramide-activated protein kinase in myeloid cells,” Journal of Biological Chemistry, vol. 269, no. 26, pp. 17606–17610, 1994.
