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M F Tsan

Publications and source records attributed to M F Tsan.

At least 37 records · Page 2Linked to original sources
PubMed1994

Protection against oxygen toxicity by tracheal insufflation of endotoxin: role of Mn SOD and alveolar macrophages.

Endotoxin and the cytokines, tumor necrosis factor and interleukin-1, are known to protect adult rats against O2 toxicity. However, whether the effect of endotoxin is mediated through its direct effect on lung cells or through cytokines is not clear. In this study, we demonstrated that endotoxin at a dosage of 5 micrograms/rat (14-20 micrograms/kg) attenuated O2-induced pulmonary injury and markedly prolonged the survival of rats exposed to 100% O2. Endotoxin was more protective when given by intratracheal insufflation or intravenous injection than by intraperitoneal injection. The endotoxin-induced O2 tolerance was associated with a selective enhancement of pulmonary manganese superoxide dismutase, but not Cu,Zn SOD, mRNA. In addition, depletion of 84% rat alveolar macrophages by liposome-encapsulated dichloromethylene diphosphonate, resulted in a marked reduction (86%) of endotoxin-induced release of tumor necrosis factor into the alveolar space. However, endotoxin was still protective in these alveolar macrophage-depleted animals.

Animals↗
PubMed1994

Induction of pulmonary Mn superoxide dismutase mRNA by interleukin-1.

We have previously demonstrated that intratracheal (IT) but not intraperitoneal (IP) administration of 5 micrograms tumor necrosis factor (TNF) or interleukin-1 (IL-1) selectively enhances pulmonary Mn superoxide dismutase (Mn SOD) mRNA, leading to increased Mn SOD protein and enzyme activity, and protects rats against O2 toxicity. In this study, we demonstrated that enhancement of pulmonary Mn SOD mRNA by TNF or IL-1 was highly dependent on the route of administration. IT insufflation of 5 micrograms TNF or IL-1 selectively enhanced levels of pulmonary but not splenic or renal Mn SOD mRNA. In contrast, IP or intravenous (i.v.) administration of TNF (5 micrograms) or IL-1 (5, 20, or 50 micrograms) had little or no effect on levels of Mn SOD mRNA in the lung, spleen, or kidney. Both TNF and IL-1, whether given by IT, IP, or i.v. administration, had no effect on levels of Cu, Zn SOD mRNA. IP administration of 2 mg/kg actinomycin D 2 h before IT insufflation of IL-1 paradoxically increased the level of pulmonary Mn SOD mRNA without affecting the level of Cu,Zn SOD or beta-actin mRNA in IL-1-treated rats. Nuclear runoff transcription assay revealed that IT insufflation of IL-1 enhanced the rate on MN SOD but not Cu,Zn SOD mRNA synthesis. We conclude that IL-1-induced increase in pulmonary Mn SOD mRNA is at least in part regulated at the transcriptional level.

Animals↗
PubMed1994

Cellular distribution of pulmonary Mn and CuZn superoxide dismutase: effect of hyperoxia and interleukin-1.

Pulmonary superoxide dismutase (SOD) plays an important role in the lung defense against O2 toxicity. We have previously demonstrated that tracheal insufflation of interleukin-1 alpha (IL-1) selectively enhances pulmonary MnSOD and protects rats against O2 toxicity. However, little is known about the cellular distribution of pulmonary MnSOD- and CuZnSOD-specific proteins. We performed immunohistochemistry in plastic sections (2 microns thick) to determine the effects of hyperoxia and IL-1 on the cellular distribution of pulmonary MnSOD and CuZnSOD in rats. MnSOD and CuZnSOD were present in all lung cells. Smooth muscle and endothelial cells appeared to contain higher immunoreactive MnSOD and CuZnSOD proteins than other lung cell types. Exposure of rats to 100% O2 for 24 hr had no effect on the cellular distribution and intensity of pulmonary MnSOD. However, at 50 hr after O2 exposure the intensity of pulmonary MnSOD was reduced. In contrast, tracheal insufflation of IL-1 markedly enhanced the intensity of pulmonary MnSOD in rats exposed to O2 for 50 hr. Neither O2 exposure nor IL-1 insufflation had any apparent effect on the distribution and intensity of pulmonary CuZnSOD. We conclude that IL-1 selectively enhances pulmonary MnSOD and that this effect is manifested in most lung cells, particularly smooth muscle and endothelial cells.

Animals↗
PubMed1993

Hyperoxic stress elevates p52(PAI-1) mRNA abundance in cultured cells and adult rat pulmonary tissue.

Hyperoxic stress alters expression of genes involved in extracellular matrix (ECM) remodeling. To identify novel ECM-associated gene products positively regulated by hyperoxia, rat kidney cells were exposed to 95% O2, and the complement of [35S]methionine-labeled, saponin-resistant, ECM-associated proteins was compared with normoxic controls. O2-stressed cells accumulated significantly greater ECM levels (approximately 3- to 4-fold that of control cells) of a 52-kDa glycoprotein (p52), recently identified as the matrix form of plasminogen activator inhibitor type 1 (PAI-1) (P.J. Higgins, P. Chaudhari, and M.P. Ryan. Biochem. J. 273: 651-658, 1991; P. J. Higgins, M. P. Ryan, R. Zeheb, T. D. Gelehrter, P. Chaudhari. J. Cell. Physiol. 143:321-329, 1990), which peaked at 48 h of exposure. Hyperoxia-associated increases in ECM p52(PAI-1) content reflected parallel elevations in p52(PAI-1) mRNA abundance. Similar results were obtained using secondary cultures of rat pulmonary fibroblasts. This 48-h period of maximal hyperoxia-induced p52(PAI-1) expression in vitro was used to design subsequent in vivo studies. Adult rats were exposed to 99% O2 for 24-50 h, and RNA was extracted from the pulmonary tissue of stressed and control animals. A 5- to 8-fold and 6- to 15-fold increase in lung p52(PAI-1) mRNA content was evident in hyperoxia-treated rats at 24 and 50 h, respectively. All of this increase occurred in the defined 3.2-kb species of rat p52(PAI-1) mRNA. Actin mRNA levels increased three- to sevenfold as a function of hyperoxic stress, whereas catalase and glyceraldehyde-3-phosphate dehydrogenase mRNA abundance was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Polyethylene glycol-conjugated superoxide dismutase protects rats against oxygen toxicity.

Superoxide dismutase (SOD) has an important role in the protection against O2 toxicity. Conjugation of Cu,Zn-SOD to polyethylene glycol (PEG-SOD) prolongs its plasma half-life and facilitates its cellular uptake. However, prior studies have shown that intravenous injection of PEG-SOD does not protect animals against O2 toxicity. In this study, we demonstrated that tracheal insufflation of PEG-SOD resulted in a dose-dependent protection against O2 toxicity. Nine of 15 rats (60%) insufflated with 25,000 U PEG-SOD survived continuous 100% O2 exposure for more than 7 days compared with control rats (n = 45), all of which died within 3 days of O2 exposure (P < 0.025). In contrast, insufflation of 25,000 U SOD, 9.7 mg methoxy-PEG (equivalent to the amount of methoxy-PEG present in 25,000 U PEG-SOD), or a combination of SOD and methoxy-PEG had no protective effect. Furthermore, intravenous or intraperitoneal injection of PEG-SOD did not afford significant protection. Protection against O2 toxicity by PEG-SOD insufflation was associated with attenuated O2-induced pulmonary injury as evidenced by a reduced volume of pleural effusion. Insufflation of PEG-SOD markedly increased pulmonary SOD activity (to 300 and 370% of controls at 24 and 50 h, respectively) without affecting pulmonary catalase activity. We conclude that insufflation of PEG-SOD protects rats against O2 toxicity, possibly by enhancing pulmonary SOD activity.

Administration, Inhalation↗
PubMed1993

Depletion of alveolar macrophages by liposome-encapsulated dichloromethylene diphosphonate.

Alveolar macrophages (AM) play an important role in lung biology. In this study, we demonstrated that tracheal insufflation of liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP-liposome) selectively depleted AMs in rats. Insufflation of a single dose of Cl2MDP-liposomes (80 microliters containing 1.34 mumol of Cl2MDP) but not liposomes containing phosphate-buffered saline resulted in > 70% depletion of AMs starting within 1 day and lasting for > 5 days after insufflation. There was a slight but significant intraalveolar inflammatory response. Insufflation of Cl2MDP also resulted in depletion of AMs; however, it caused cytoplasmic edema of alveolar epithelial cells as well. Depletion of AMs by Cl2MDP-liposomes markedly reduced the endotoxin-induced neutrophil (polymorphonuclear lymphocyte) recruitment and the release of tumor necrosis factor into the alveolar space, suggesting that endotoxin-induced neutrophil recruitment and tumor necrosis factor release were dependent on AMs. This AM-depleted animal model will be useful for studying the in vivo functions of AMs and their role in various physiological and pathological conditions.

Animals↗
PubMed1993

Superoxide dismutase and pulmonary oxygen toxicity.

Three forms of superoxide dismutase (SOD) exist in the lung: CuZnSOD, MnSOD and extracellular SOD. Evidence suggests that both CuZnSOD and MnSOD are important in pulmonary defense against oxygen toxicity. Enhancement of pulmonary levels of CuZnSOD by transgenic overexpression of CuZnSOD, or tracheal insufflation of liposome-encapsulated or polyethylene glycol-conjugated CuZnSOD, protects animals against oxygen toxicity. Likewise, transgenic overexpression of MnSOD, or induction of endogenous MnSOD by endotoxin, tumor necrosis factor, or interleukin 1, also protects animals against oxygen toxicity. The role of extracellular SOD in the pulmonary defense against oxygen toxicity is not clear.

Animals↗
PubMed1992

Cyclosporine and prednisone therapy for pure red cell aplasia in patients with chronic lymphocytic leukemia.

We describe the characteristics of response to treatment with cyclosporine (CYA) plus prednisone in seven episodes of pure red cell aplasia (PRCA) in four patients with B cell chronic lymphocytic leukemia (CLL). Fourteen episodes of PRCA occurred in four patients with CLL. Eleven episodes were treated with conventional therapies which included an alkylating agent and prednisone. Four episodes that failed to respond to conventional therapies and an additional three episodes were treated with CYA and prednisone. Six of the seven episodes, including three of four which had failed conventional therapies, responded to CYA plus prednisone compared with six of eleven episodes treated with conventional therapies. Response to CYA and prednisone occurred without a reduction in leukemic mass. In contrast, PRCA remission did not occur until after leukemic mass reduction in three of four patients treated successfully with conventional therapies. Time to response was shorter (14 +/- 3 days) with CYA plus prednisone than with conventional therapies (154 +/- 97 days) in three of four patients. These results indicate that CYA plus prednisone is an effective therapy for the induction of remission from PRCA in patients with CLL.

Cyclosporine↗
PubMed1992

D-factor and growth hormone enhance tumor necrosis factor-induced increase of Mn superoxide dismutase mRNA and oxygen tolerance.

D-Factor (differentiation-inducing factor or leukemia inhibitory factor) and growth hormone are proteins that regulate growth and differentiation of cells. In this study, we demonstrated that recombinant human D-factor and growth hormone caused a slight but significant protection of adult rats against oxygen toxicity without affecting levels of pulmonary manganous superoxide dismutase (MnSOD) mRNA. D-Factor and growth hormone also markedly enhanced tumor necrosis factor (TNF)-induced oxygen tolerance. This latter effect was associated with a marked enhancement of TNF-mediated induction of pulmonary MnSOD mRNA.

Animals↗
PubMed1992

Hyperoxia increases plasminogen activator activity of cultured endothelial cells.

Confluent calf pulmonary artery endothelial monolayers exposed to 95% oxygen for 1, 2, or 3 days exhibit a time-dependent increase in adherence to substratum, which closely parallels changes in actin cytoarchitecture and the distribution of focal contact proteins vinculin and talin. Oxygen exposure also resulted in elevated plasminogen activator (PA) activity in conditioned media (CM) and in cytoskeletal protein- and focal contact protein-enriched fractions, with highest levels achieved in the latter two fractions at 48 h after oxygen exposure. PAs have been shown to participate in dismantling of extracellular matrix in a number of physiological and pathological situations. Immunocytochemical studies demonstrated extensive restructuring of matrix proteins collagen IV, laminin, and fibronectin, which correlated temporally with elevated PA levels. Further, when protease-containing cell fractions were used to study degradation of isolated matrices, those obtained from hyperoxia-exposed cells were substantially more active than those from normoxia-exposed cells. Our data suggest that hyperoxia-induced production of PA (and perhaps other proteases) may be partly responsible for degradation of the extracellular matrix of endothelial cells.

Animals↗
PubMed1992

IL-6 enhances TNF-alpha- and IL-1-induced increase of Mn superoxide dismutase mRNA and O2 tolerance.

Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1), and interleukin-6 (IL-6) are multifunctional cytokines produced by a number of cells in response to endotoxin. We have previously demonstrated (M.-F. Tsan, J. E. White, T. A. Santana, and C. Y. Lee. J. Appl. Physiol. 68: 1211-1219, 1990, and M.-F. Tsan, C. Y. Lee, and J. E. White. J. Appl. Physiol. 71: 688-697, 1991) that tracheal insufflation of 5 micrograms of TNF-alpha or 1 microgram of IL-1 markedly protects rats against O2 toxicity and enhances pulmonary Mn superoxide dismutase (Mn SOD) activity. We now report that TNF-alpha and IL-1 at subprotective doses, e.g., 1 and 0.2 micrograms, respectively, act synergistically in protecting rats against O2 toxicity. Likewise, TNF-alpha and IL-1 at 0.005 microgram/ml each act synergistically in enhancing endothelial cell Mn SOD, but not Cu,Zn SOD mRNA levels. IL-6 at 5 or 10 micrograms provides no protective effect in rats against O2 toxicity and at up to 0.5 microgram/ml has no apparent effect on endothelial cell Mn or Cu,Zn SOD mRNA levels. However, IL-6 markedly enhances TNF-alpha- and IL-1-induced increases in Mn SOD mRNA levels and O2 tolerance. These results support an important role of Mn SOD in the protection against O2 toxicity.

Animals↗
PubMed1992

Kinetics of pulmonary superoxide dismutase in interleukin-1-induced oxygen-tolerant rats.

We have previously demonstrated that tracheal insufflation of interleukin-1 alpha (IL-1) enhances pulmonary Mn superoxide dismutase (Mn SOD) activity and protects rats against O2 toxicity (M. F. Tsan, C. Y. Lee, and J. E. White. J. Appl. Physiol. 71: 688-697, 1991). In this study, we investigated the kinetics of mRNA, specific (immunoreactive) proteins, and enzyme activities of pulmonary Mn SOD and Cu,Zn SOD in IL-1-induced O2-tolerant rats. At 1 day after IL-1 (5 micrograms) insufflation and O2 exposure, levels of Mn SOD mRNA and specific protein, but not enzyme activity, were markedly elevated. At 2.3 and 7 days after O2 exposure, levels of Mn SOD mRNA, specific protein, and enzyme activity were all increased in IL-1-treated animals. In contrast, in control rats at 2.3 days after O2 exposure, level of Mn SOD mRNA was markedly elevated, whereas levels of specific protein and enzyme activity were decreased. Levels of pulmonary Cu,Zn SOD mRNA, specific protein, and enzyme activity were unchanged in control and IL-1-treated rats, except that in IL-1-induced long-term O2-tolerant rats (7 days after O2 exposure), they were all increased. Since at 7 days after IL-1 insufflation, normoxia-exposed rats did not show increased levels of pulmonary Mn SOD or Cu,Zn SOD mRNA, the increased levels of pulmonary SOD seen in IL-1-induced long-term O2-tolerant rats are, at least in part, due to the effect of O2 exposure.

Animals↗
PubMed1991

Interleukin 1 protects rats against oxygen toxicity.

We studied the effect of interleukin 1 alpha (IL-1) in the protection against O2 toxicity. Tracheal insufflation of IL-1 resulted in a dose-dependent protection against O2 toxicity. All control rats died within 3 days of O2 exposure. In contrast, 84, 71, and 20% of rats insufflated with 5, 1, and 0.2 microgram(s) IL-1 (150, 30, and 6 x 10(4) U), respectively, survived 100% O2 exposure for greater than 11 days. At 2.3 days after O2 exposure, control rats showed severe pulmonary injury, which insufflation of 5 microgram(s) IL-1 markedly attenuated. The protection against O2 toxicity was associated with a selective enhancement of pulmonary Mn-superoxide dismutase (Mn-SOD) activity in IL-1-insufflated rats. In rats insufflated with IL-1 that survived exposure to 100% O2 for 7 days, the activities of pulmonary Mn-SOD, Cu,Zn-SOD, catalase, and glutathione peroxidase were all increased. The increased pulmonary Mn-SOD activity demonstrated in IL-1-insufflated rats at 2.3 days after O2 exposure may contribute to the protection against acute O2 toxicity, and the markedly increased activities of all pulmonary antioxidant enzymes shown in rats insufflated with IL-1 that survived O2 exposure for 7 days may in part be responsible for the chronic adaptation of these rats to a 100% O2 environment.

Animals↗
PubMed1991

Erythrocyte insufflation-induced protection against oxygen toxicity: role of cytokines.

We studied the pulmonary response of adult rats to erythrocyte (RBC) and RBC lysate insufflation to define the mechanism of RBC insufflation-induced protection against oxygen toxicity. Tracheal insufflation of 1 ml RBC (75%) or RBC lysate induced an intense pulmonary inflammatory response. Within 24 h of oxygen exposure, greater than 95% of insufflated RBCs was hemolyzed. The cell-free fraction of alveolar lavage fluids from RBC- or RBC lysate-insufflated rats had similar capacity in protecting endothelial cells against H2O2 cytotoxicity. However, RBC insufflation but not RBC lysate insufflation, protected rats against oxygen toxicity. There was marked erythrophagocytosis by alveolar macrophages of RBC-insufflated rats. Insufflation of RBCs, but not RBC lysate, resulted in production of tumor necrosis factor and interleukin 1, which could be recovered by bronchoalveolar lavages. When rats were insufflated with a combination of RBC lysate and cytokines at dosages within the range of cytokine levels achievable in alveolar lavage fluids by RBC insufflation, they became tolerant to oxygen. These results suggest that endogenously produced tumor necrosis factor and interleukin-1 as a result of RBC insufflation may play an important role in RBC insufflation-induced oxygen tolerance.

Animals↗
PubMed1991

Tumor necrosis factor enhances endothelial cell susceptibility to oxygen toxicity: role of glutathione.

The effect of tumor necrosis factor-alpha (TNF) on hyperoxia-induced endothelial injury in vitro was investigated. TNF caused a time- and dose-dependent reduction in the number of viable pulmonary artery endothelial cells. The TNF-mediated endothelial cytotoxicity was more pronounced under hyperoxia (95% O2 and 5% CO2) than under normoxia (95% air and 5% CO2). Pretreatment of endothelial cells with TNF (0.01 micrograms/ml or 240 U/ml) for 18 h at normoxia reduced the intracellular concentration of total glutathione (GSH), whereas the concentration of oxidized GSH was increased. These TNF-treated endothelial cells were more susceptible to hyperoxia- or hydrogen peroxide-mediated cytotoxicity. TNF also induced changes in endothelial morphology and in the distribution and density of actin filaments. Exogenous GSH or L-2-oxothiazolidine-4-carboxylate, which enhanced endothelial GSH concentrations, partially protected endothelial cells against TNF-mediated cytotoxicity, morphologic changes, and actin filament redistribution, especially under the hyperoxic condition. These results suggest an important role of GSH in modulating endothelial response to TNF.

Actins↗
PubMed1990

The substrate-associated protein p45 of porcine endothelial cells: multiple isoforms, cytoskeletal-like properties and induction by hyperoxic stress.

1. Cultured mesenchymal cells respond to hyperoxic (hyper-O2) stress with increased cell flattening/substrate adhesion and overall 47-69% reductions in total matrix-associated (i.e. saponin-resistant [SAP fraction]) protein. 2. Electrophoretic analysis revealed a selective hyper-O2-related 2.7- to 4-fold increase in SAP and cytoskeletal fraction deposition of the protein p45 beginning early (within 12 hr) after initial exposure of porcine endothelial cells to hyper-O2 and increasing over a 48 hr period. 3. p45 consisted of 8 distinct isoforms differing only in pI; hyper-O2-augmented matrix deposition of 3. p45 consisted of 8 distinct isoforms differing only in pI; hyper-02-augmented matrix deposition of p45 involved all 8 isoforms with the more basic subtypes exhibiting slightly greater net increases. 4. Both the specificity and time course of p45 induction, relative to the onset of hyper-O2 cytoarchitectural remodeling, indicate that p45 up-regulation constitutes an early aspect of the hyper-O2 adaptive response.

Actins↗
PubMed1990

Molecular basis for tumor necrosis factor-induced increase in pulmonary superoxide dismutase activities.

Tracheal insufflation of tumor necrosis factor (TNF) enhances pulmonary antioxidant enzyme activities and protects rats against oxygen toxicity (J. Appl. Physiol. 68: 1211-1219, 1990). We now report that tracheal insufflation of TNF selectively induced pulmonary Mn-superoxide dismutase (SOD) mRNA in normoxia- and hyperoxia-exposed rats, leading to increased amounts of Mn-SOD specific protein and enzyme activity. Tracheal insufflation of TNF had no effect on the levels of pulmonary Cu,Zn-SOD mRNA or specific protein. Hyperoxia alone also selectively induced pulmonary Mn-SOD mRNA. However, the hyperoxia-induced increase in Mn-SOD mRNA was not associated with an increase in Mn-SOD specific protein or enzyme activity. The results suggest that the increased pulmonary Mn-SOD in TNF-insufflated rats may contribute to the TNF-induced protection against oxygen toxicity.

Animals↗