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Biomedical subjects

M Takeya

Publications and source records attributed to M Takeya.

At least 73 records · Page 4Linked to original sources
PubMed1997

The multiple roles of macrophage scavenger receptors (MSR) in vivo: resistance to atherosclerosis and susceptibility to infection in MSR knockout mice.

Both type I and type II MSRs are integral membrane proteins containing a collagenous domain and elicit an extraordinarily wide range of ligand binding capability. They were found during the search for the molecule(s) responsible for the accumulation of modified LDL during atherogenesis. However, all prior the evidence relating to their physiological and pathophysiological roles in vivo had been indirect. Targeted disruption of the MSR gene results in a reduction in the size of atherosclerotic lesions in an apo E deficient animal. Macrophages from MSR deficient mice exhibit a marked decrease in modified LDL uptake in vitro, whereas modified LDL clearance from plasma remains normal, suggesting that there are alternative mechanisms for the uptake of modified LDL from the circulation. In addition, MSR knockout mice are more susceptible to L. monocytogenes and HSV-1 infection, indicating a role for MSR in host defense against various pathogens.

Animals↗
PubMed1996

Coinduction of nitric oxide synthase, argininosuccinate synthetase, and argininosuccinate lyase in lipopolysaccharide-treated rats. RNA blot, immunoblot, and immunohistochemical analyses.

Nitric oxide (NO) is synthesized from arginine by nitric oxide synthase (NOS), and citrulline which is generated can be recycled to arginine by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL). Rats were injected with bacterial lipopolysaccharide (LPS), and expression of the inducible isoform of NOS (iNOS), AS, and AL was analyzed. In RNA blot analysis, iNOS mRNA was undetectable before the LPS treatment but was induced by LPS in the lung, heart, liver, and spleen, and less strongly in the skeletal muscle and testis. AS mRNA was induced in the lung and spleen, and AL mRNA was weakly induced in these tissues. AS and AL mRNAs were abundant in the control liver and remained unchanged after the treatment. Kinetic studies showed that iNOS mRNA increased rapidly in both spleen and lung, reached a maximum 2-5 h after the treatment, and decreased thereafter. On the other hand, AS mRNA increased more slowly and reached a maximum in 6-12 h (by about 10-fold in the spleen and 2-fold in the lung). AL mRNA in the spleen and lung increased slowly and remained high up to 24 h. In immunoblot analysis, increase of iNOS protein was evident in the lung, liver, and spleen, and there was an increase of AS protein in the lung and spleen. In immunohistochemical analysis, macrophages in the spleen that were negative for iNOS and AS before LPS treatment were strongly positive for both iNOS and AS after this treatment. As iNOS, AS, and AL were coinduced in rat tissues and cells, citrulline-arginine recycling seems to be important in NO synthesis under the conditions of stimulation.

Animals↗
PubMed1996

Z-DNA-forming sites within the human beta-globin gene cluster.

Agarose-encapsulated, metabolically active, permeabilized nuclei from human hematopoietic cell lines were tested for Z-DNA formation in the beta-globin gene cluster. Biotinylated monoclonal antibodies against Z-DNA were diffused into the nuclei and cross-linked to DNA with a 10-ns laser exposure at 266 nm. Following digestion with restriction enzymes, fragments that had formed Z-DNA were isolated. Seventeen regions with Z-DNA sequence motifs in the 73-kb region were studied by PCR amplification, and five were found in the Z conformation.

Cells, Cultured↗
PubMed1996

AM-3K, a novel monoclonal antibody specific for tissue macrophages and its application to pathological investigation.

An anti-human macrophage monoclonal antibody, AM-3K, was produced using human alveolar macrophages as antigen. The molecular weights of the antigen recognized by AM-3K were 120 and 70 kD. Immunohistochemically, AM-3K reacted intensely with most macrophages in lymphoreticular organs and in many other organs and tissues. In the spleen, AM-3K reacted with red pulp macrophages, some white pulp macrophages, and tingible body macrophages in lymphoid follicles. In the lymph nodes, many macrophages distributed in the outer cortex, paracortical area, medulla, capsule, or within lymphoid follicles showed an intense reaction for AM-3K. Kupffer cells of the liver, macrophages in the connective tissues, and interstitial macrophages of the kidneys, pancreas, testis, and many other organs were also strongly labelled. AM-3K also reacted with macrophages in many pathological conditions. This antibody, however, did not react with dendritic cell populations, such as epidermal Langerhans cells, interdigitating cells in the paracortex of the lymph nodes, and follicular dendritic cells within the lymphoid follicles, nor with cells other than macrophages, including epithelial cells, vascular endothelial cells, lymphocytes, and granulocytes. Reaction products for AM-3K were found on the cytoplasmic membrane of macrophages by immunoelectron microscopy. In both cryostat sections and formalin-fixed paraffin sections, this monoclonal antibody recognized the antigen present on the cell surface membrane of tissue macrophages, but not monocytes or dendritic cells.

Antibodies, Monoclonal↗
PubMed1996

IL-8/NAP-1 is the major T-cell chemoattractant in synovial tissues of rheumatoid arthritis.

T-cell infiltration into synovium is a crucial process for rheumatoid arthritis (RA). To investigate the mechanism of T-cell infiltration, we studied T-cell attracting activity in synovial tissue extracts of RA or osteoarthritis (OA) whose synovium lacks T-cell accumulation. RA extracts attracted twofold more T cells than OA extracts. By gel filtration column chromatography the activity of RA extracts was separated into two peaks; one was eluted at the 67-kDa region and the other was at the 12-kDa region, while the latter was absent in OA extracts. The activity eluted at the 12-kDa region was absorbed mostly by an antibody against IL-8/NAP-1, a potent T-cell chemotactic factor. IL-8/NAP-1 concentrations in RA extracts were much higher than those in OA extracts and correlated to T-cell attracting activity eluted at the 12-kDa region. The checkerboard analysis revealed that the 67-kDa activity was chemokinetic but not chemotactic. These results suggest that IL-8/NAP-1 is the major T-cell chemoattractant in RA-synovium.

Aged↗
PubMed1996

Expression of adhesion molecules and monocyte chemoattractant protein -1 (MCP-1) in the spinal cord lesions in HTLV-I-associated myelopathy.

Leukocyte adhesion molecules to endothelium plays an important role in the pathogenesis of inflammatory diseases, including HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). To help define the role of adhesion molecules in HAM/TSP, we studied the expression of lymphocyte function-associated antigen-1 (LFA-1), Mac-1, very late antigen-4 (VLA-4), Sialyl Lewisx (SLex), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1) and monocyte chemoattractant protein-1 (MCP-1) in the spinal cord lesions of HAM/TSP. The results indicate that spinal cord lesions of HAM/TSP have greater VCAM-1 expression on endothelium compared with those of controls. Infiltrating mononuclear cells, especially perivascular lesions, expressed VLA-4. Although the expression of ICAM-1 in the spinal cords was not distinctive between HAM/TSP and controls, infiltrating mononuclear cells in the spinal cords of HAM/TSP strongly expressed LFA-1 and Mac-1. ELAM-1 was expressed on endothelium in the inactive-chronic lesions from three of five HAM/HAM/TSP, but was not detectable in the spinal cords of controls. SLex reactions was detectable on occasional perivascular cells in the spinal cord of HAM/TSP, but not in those controls. MCP-1 was detectable on perivascular infiltrating cells and vascular endothelium in active-chronic lesions. This study suggest that VLA-4/VCAM-1 interaction may play an important role for lymphocyte migration into the central nervous system (CNS) and MCP-1 may also be involved in inflammatory cell recruitment to the CNS in HAM/TSP.

Aged↗
PubMed1996

Development and heterogeneity of macrophages and their related cells through their differentiation pathways.

Macrophages are a heterogeneous population differing in their site of location, morphology and function. They develop from hematopoietic stem cells originating in both fetal and bone marrow hematopoiesis. In yolk sac and early hepatic hematopoiesis, primitive/fetal macrophages develop from hematopoietic stem cells, bypassing the stage of monocytic cells (monoblasts, promonocytes and monocytes), possess proliferative capacity and differentiate into resident macrophages in tissues in late ontogeny. Monocytic cells develop in hepatic hematopoiesis after the development of primitive/fetal macrophages, then move into the bone marrow in late ontogeny, forming a monocyte-derived macrophage population in tissues. Like monocytes, the monocyte-derived macrophages have no proliferative potential and are short-lived, whereas the resident macrophages are long-lived in tissue, possess proliferative capacity and can be sustained by self-renewal. In adult life, the bone marrow releases macrophage precursors (immature myeloid cells) and monocytes into peripheral blood, but normally not monoblasts or promonocyts. The myeloid precursor cells migrate into tissues and differentiate into resident macrophages or related cells in situ due to macrophage differentiation or growth factors, such as M-CSF and GM-CSF, produced in situ and/or supplied humorally. Monocytes, however, migrate into tissues in response to inflammatory stimuli and differentiate into exudate macrophages. The distinct differentiation pathways of monocyte/macrophages, resident macrophages, other macrophage subpopulations, and macrophage-related cells are reviewed together with the heterogeneity of macrophage precursor cells.

Animals↗
PubMed1996

Interspecies reactivities of anti-human macrophage monoclonal antibodies to various animal species.

We examined interspecies reactivities of eight anti-human monocyte/macrophage monoclonal antibodies (MAbs), Am-3K, PM-2K, X4, X14, Ber-MAC3, GHI/61, EBM/11, and KP1, with various animal tissues including rats, guinea pigs, rabbits, cats, dogs, goats, pigs, bovines, horses, and monkeys. All MAbs recognized monkey macrophages. Pig macrophages were detected by most MAbs except for EBM/11 and KP1. Of the eight antibodies, AM-3K showed the widest interspecies reactivity. It reacted with macrophages of all animal species examined, except for rats. Western blot analysis revealed a similarity in the antigens recognized by AM-3K among guinea pigs, rabbits, and humans. Other anti-human MAbs demonstrated distinct reactive patterns against macrophages in animals. The immunostaining patterns of all of these MAbs in animal tissues were similar to those found in humans, although some MAbs, such as AM-3K, EBM/11, and X4, displayed more restricted reactivity in animals than in humans. These results indicate that some anti-human monocyte/macrophage MAbs are also available for immunohistochemical detection of monocyte/macrophages in animal tissues. Among them, AM-3K is considered to be the most useful MAb for identifying macrophages in various tissues of animals.

Animals↗
PubMed1996

Heterogeneity in the origin and immunophenotypes of "histiocytic" cells in transplantable rat malignant fibrous histiocytoma.

To clarify the origin and nature of "histiocytic" cells in malignant fibrous histiocytoma (MFH), immunoreactivities to rat macrophage/histiocyte-specific monoclonal antibodies (ED1 and ED2) and monocyte chemoattractant protein-1 (MCP-1) production were investigated using rat transplantable MFH-derived cloned cells (undifferentiated MT-8 and fibrohistiocytic MT-9). In different cultures, the positive rates for ED1 and ED2 ranged from 2.5% to 26.0% in MT-8, and from 6.0% to 40.0% in MT-9. In homotransplants, ED1-positive cells were frequently observed in MT-9 tumors, but barely seen in MT-8 tumors. In both MT-8 and MT-9 tumors, ED2-positive cells were not detected within tumors. Immunophenotypic characteristics of MT-8 and MT-9 to these antibodies seemed to be easily altered depending on in vitro and in vivo conditions. By ELISA, MCP-1 was hardly detected in culture supernatants of MT-8 and MT-9, but its level was very high in sera of MT-8- and MT-9-tumor-bearing rats. In rats with these tumors, the number of circulating monocytes was significantly increased and the presence of factors stimulating macrophage proliferation was demonstrated by the colony formation assay using rat bone marrow cells. Histiocytic cells in MT-8 and MT-9 tumors that were produced in nude mice reacted only with antibody to mouse macrophage-associated antigen. This suggests the existence of non-neoplastic, infiltrated macrophages of host origin that were induced probably by MCP-1 and factors stimulating macrophage proliferation. The present studies indicate the presence of heterogeneities in the origin and immunophenotypes of "histiocytic" cells in rat MFH.

Animals↗
PubMed1996

Fas/Apo-1 (CD95)-mediated and CD95-independent apoptosis of malignant plasma cells.

CD95 (Fas/Apo-1) mediates apoptosis in cells of various types. Expression of CD95 and its function were investigated in myeloma cells and most plasma cell lines have been found to be CD95-positive. Anti-CD95 antibody induced apoptosis in these cell lines in a manner dependent on intensity of CD95 expression. Bel-2 expression levels in these cell lines were not correlated with sensitivity to CD95-induced apoptosis. Myeloma cells from approximately 70% of cases analyzed expressed CD95, suggesting a high frequency of CD95 expression of myeloma cells. The incidence of CD95 expression in samples from extramedullary lesions were higher than those of bone marrow myeloma cells. Anti-CD95 antibody did not induce apoptosis in some freshly isolated myeloma cells despite the expression of CD95 induced apoptosis in myeloma cell lines in a manner dependent on intensity of CD95 expression. In fresh samples, intensity of CD95 expression was not correlated with apoptosis evoked by anti-CD95 antibody. Interestingly, isolated myeloma cells with an high-level expression of CD95 showed spontaneous apoptosis during in vitro incubation. This was observed in samples from cases with high serum levels of lactate dehydrogenase (LDH), suggesting that the LDH was derived from cells undergoing spontaneous apoptosis in vivo. Taken together, CD95 is expressed in most myeloma cell lines and in many freshly isolated myeloma cells. However, some of the latter escape from CD95-dependent apoptosis despite the expression of CD95. Moreover, some myeloma cells from cases with aggressive disease may undergo apoptosis in a CD95-independent manner. In this review, the significance of CD95 and apoptosis of myeloma cells are discussed.

Animals↗
PubMed1996

Immunohistochemistry of new type I alveolar epithelial cell markers of the rat.

The presence of pan-cadherin and the MEP-I antigen in normal and diseased rat lung was established by employing immunoperoxidase and double label fluorescence techniques. The binding of a mouse monoclonal antibody (MEP-1) reacting specifically with type I pneumocytes was assessed on paraffin sections of normal specimens as well as those with pulmonary fibrosis induced by bleomycin or radiation treatment. In injured alveolar epithelium, a diminished type I cell and a focal type II cell immunoreactivity was found. Electron microscopy of immunogold-labelled lung tissue confirmed the type I cell specificity of MEP-1. In severely injured pulmonary parenchyma MEP-1-negative areas occurred, which were also negative with the type II pneumocyte marker Maclura pomifera lectin. Similarly, a polyclonal pan-cadherin antibody uniformly decorated luminal surfaces of alveoli except the type II pneumocytes. Furthermore, pleural mesothelial cells, bronchiolar epithelial cells, endothelial cells of large blood vessels and alveolar macrophage surfaces exhibited pan-cadherin immunoreactivity. After injury, a remarkable loss of pan-cadherin immunoreactivity in the MEP-1-positive type I epithelial cells was detectable. These findings suggest that characterization of normal alveolar epithelial cells and monitoring of the epithelial remodelling in pulmonary pathohistology are sufficiently described by the antibodies MEP-1 anti pancadherin.

Animals↗
PubMed1996

Expression of inducible nitric oxide synthase and its involvement in pulmonary granulomatous inflammation in rats.

Two types of pulmonary granulomatosis were produced in rats by intratracheal instillation of zymosan or silica. In both models, immunostaining with anti-rat monoclonal antibody for inducible nitric oxide synthase (iNOS), ANOS11, showed that the intensity of iNOS immunoreactivity in the inflammatory lesions peaked at 3 days and declined thereafter. Immunohistochemical double staining and in situ hybridization demonstrated the expression of iNOS in neutrophils, monocyte-derived macrophages, and bronchiolar epithelial cells in the pulmonary lesions. Electron spin resonance spectroscopy revealed the production of an excessive amount of nitric oxide (NO) in the pulmonary lesions. Immunostaining with a polyclonal antibody against nitrotyrosine indicated the formation of nitrotyrosine residues in the granulomatous lesions, particularly in the periphery of the lesions, providing indirect evidence for the generation of peroxynitrite anion in the zymosan- or silica-instilled lungs. Administration of N omega-nitro-L-arginine methyl ester or S-methylisothiourea sulfate, which significantly suppressed NO production, resulted in marked reduction of monocyte/macrophage infiltration as well as in inhibition of induction of monocyte chemoattractant protein-1 in the lesions. These data indicate that NO and its more reactive product peroxynitrite anion may be important mediators of granuloma formation in the lung.

Animals↗
PubMed1995

Terminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein.

STK, a new member of the hepatocyte growth factor receptor family, is the receptor for macrophage-stimulating protein (MSP), which acts on murine resident peritoneal macrophages. We established polyclonal and monoclonal antibodies against STK and characterized the structure of STK protein and STK expression on cells of the mononuclear phagocyte system. Western blotting showed that the STK transcript is translated into a single-chain precursor and then cleaved into a 165-kD disulfide-linked heterodimer composed of a 35-kD alpha-chain and a 144-kD beta-chain. Western blotting detected STK protein on resident peritoneal macrophages, a target of MSP, and showed that it was autophosphorylated in cells stimulated by MSP. By flow cytometric analysis using a monoclonal anti-STK antibody, we showed that STK protein is expressed on restricted macrophage populations such as resident peritoneal macrophages, but not on exudate peritoneal macrophages or mononuclear phagocytes of the bone marrow, peripheral blood, spleen, or alveoli. Resident peritoneal macrophages were classified into two fractions according to their reactivity with an anti-STK antibody and a marker antibody for macrophages: STKhigh-F4/80high cells and STKnegative-F4/80low cells. Acute exudative macrophages were all STKnegative-F4/80low, but they gradually became predominantly STKhigh-F4/80high several days after entrance into the peritoneal cavity. These results showed that after monocytes migrate into the peritoneal cavity, they undergo terminal differentiation in the peritoneal microenvironment. This is the first evidence of tissue-specific terminal differentiation of peritoneal macrophages, and this terminal differentiation can be characterized by the expression of STK receptor tyrosine kinase.

Animals↗
PubMed1995

Expression of Fas/Apo-1 (CD95) and apoptosis in tumor cells from patients with plasma cell disorders.

Fas/Apo-1 antigen (CD95) is a cell surface molecule that directly mediates apoptosis. Fas expression was studied in five plasma cell lines, 11 multiple myeloma cases, and three plasma cell leukemia (PCL) cases. Induction of apoptosis by anti-Fas antibody was studied in five plasma cell lines and fresh plasma cells from eight patients. Apoptosis was confirmed by morphologic analysis alone or in combination with DNA electrophoresis analysis. Four of the five cell lines showed Fas expression, three of which showed induction of apoptosis by anti-Fas antibody. One cell line, RPMI 8226, showed the highest sensitivity for Fas-mediated apoptosis. High bcl-2 expression was found in KMS12PE, which showed resistance to Fas-mediated apoptosis despite its Fas expression. Plasma cells from seven fresh cases, including all five cases with high serum lactate dehydrogenase (LDH), showed expression of Fas antigen. Fas-induced apoptosis was found in five cases at various levels, although significant induction of apoptosis was found in only one case. Interestingly, Fas-independent apoptosis was induced during culture without anti-Fas antibody in cases with high serum LDH. These results indicate that plasma cells from aggressive myeloma with high LDH express Fas antigen and undergo apoptosis through either Fas-mediated or Fas-independent pathways. An understanding of the mechanism of apoptosis in malignant plasma cells should contribute to investigations of the pathophysiology of and therapy for myeloma/PCL.

Adult↗
PubMed1995

Localization of advanced glycation end products of Maillard reaction in bovine tissues and their endocytosis by macrophage scavenger receptors.

In aged bovines, the accumulation of advanced glycation end-products (AGEs) in macrophages, endothelial cells, adventitial cells, or pericytes; epithelial or parenchymal cells of some organs such as the liver, adrenals, and kidneys; neuronal cells in the brain; and extracellular matrix was demonstrated by immunohistochemistry using anti-AGE monoclonal antibody 6D12. Immunoelectron microscopy demonstrated the localization of AGEs in the endosomal and lysosomal compartments of various types of cell and in the extracellular matrix. By biochemical characterization of the interaction of AGEs with bovine alveolar macrophages using [125I]AGE-bovine serum albumin (BSA), the cell association and subsequent endocytic degradation of [125I]AGE-BSA were confirmed. To investigate the possible participation of scavenger receptors in the endocytosis of AGEs, these cells were incubated with AGE-BSA conjugated with colloidal gold particles (AGE-BSA-Au particles) and examined by immunoelectron microscopy with a monoclonal antibody for bovine macrophage scavenger receptors, D2. In these macrophages, AGE-BSA-Au particles were bound to the D2-positive scavenger receptors on the surface membrane, endocytosed, and directed to secondary lysosomes. The scavenger receptors were dissociated from the ligands in late endosomes and recycled via a trans-Golgi system to the cell surface membrane. These data suggest that scavenger receptors participate in the endocytic process of AGEs by macrophages.

Aging↗
PubMed1995

Production of monocyte chemoattractant protein-1 by bovine glomerular endothelial cells.

To explore the role of glomerular endothelial cells (GEN) in the pathogenesis of glomerulonephritis, the in vitro production of monocyte chemoattractant protein-1 (MCP-1) by bovine GEN was determined by chemotaxis assay, and Western blot analysis, and immunocytochemistry. Monocyte chemotactic activity of GEN-conditioned media was detectable by a chemotaxis assay using human peripheral blood monocytes. Exposure to human recombinant interleukin-1 beta (IL-1 beta) and phorbol myristate acetate (PMA) significantly increased the chemotactic activity of GEN-conditioned media. A checkerboard analysis showed that the response of monocytes to GEN-conditioned media was truly chemotactic. Immunoadsorption with a monoclonal antibody to human MCP-1 reduced the chemotactic activity of GEN-conditioned media by 85%. Northern blot analysis revealed that MCP-1 mRNA was constitutively expressed by GEN and that IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) increased MCP-1 mRNA levels in a dose- and time-dependent manner. Furthermore, PMA induced an increase in MCP-1 mRNA levels, whereas dibutyryl cyclic AMP and forskolin had minimal effects. Inhibition study using protein kinase inhibitors revealed that MCP-1 mRNA expression induced by IL-1 beta and TNF-alpha was suppressed by the tyrosine kinase inhibitor genistein, not by the protein kinase C inhibitors staurosporine or H-7, or the protein kinase A inhibitor H-89, suggesting an important role of tyrosine kinase in the cytokine-induced MCP-1 gene expression. Dexamethasone had a small inhibitory effect on constitutive MCP-1 mRNA expression, but no effect on the induction by TNF-alpha. By immunoperoxidase staining and Western blot analysis using an anti-MCP-1 monoclonal antibody. MCP-1 protein was detected in untreated GEN and increased by exposure to TNF-alpha. These results demonstrate the cytokine-induced production of MCP-1 by GEN at gene and protein levels as well as bioactivity, and suggest that GEN may participate in the development of glomerulonephritis through the production of MCP-1.

Blotting, Northern↗
PubMed1995

Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in reversible endotoxic shock studied by a novel monoclonal antibody against rat iNOS.

An antirat monoclonal antibody (mAb) against inducible nitric oxide synthase (iNOS), ANOS11, was used for immunohistochemistry to examine the expression of iNOS in various organs and tissues of adult rats in experimental endotoxic shock induced by lipopolysaccharide (LPS) injection. The phenotype of iNOS-expressed cells was also examined immunohistochemically using various mAbs. In control rats, very few cells were positive for ANOS11 except in the thymus. After intravenous injection of LPS, the number of iNOS-positive cells increased rapidly in almost all organs, except the thymus and brain, peaked 6 h after the injection, and decreased slowly. Of the numerous inflammatory cells that infiltrated the lungs, liver, and spleen after LPS injection, many were positive for ANOS11. Besides inflammatory cells, hepatocytes and endothelial cells of the aorta were also positive for ANOS11 but only around 6 h after injection. The cellular composition of iNOS-positive infiltrated cells changed along with the progression of endotoxic shock. At 4 to 6 h after injection, most iNOS-positive cells were considered polymorphonuclear leukocytes judging by their positive reactivity to OX42 and their nuclear morphology. The population of iNOS-positive macrophages positive for ED1 or ED2 increased with time. After 24 h, many iNOS-positive macrophages were found around the focal necrosis in the liver and spleen. These results indicate that the expression of iNOS in neutrophils, endothelial cells, and hepatocytes precedes that of macrophages in experimental endotoxic shock. The expression of iNOS in various cells and organs is closely associated with the progress and pathological changes of endotoxic shock.

Amino Acid Oxidoreductases↗