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Biomedical subjects

D L Laskin

Publications and source records attributed to D L Laskin.

At least 19 recordsLinked to original sources
PubMed2001

Tissue injury following inhalation of fine particulate matter and hydrogen peroxide is associated with altered production of inflammatory mediators and antioxidants by alveolar macrophages.

Hydrogen peroxide (H(2)O(2)) is present in the atmosphere at concentrations known to induce cell and tissue damage. However, inhaled H(2)O(2) vapor should not reach the lower lung due to its high water solubility. It has been suggested that hygroscopic components of particulate matter (PM) may transport H(2)O(2) into the lower lung and induce tissue injury and this was investigated. Ammonium sulfate [(NH(4))(2)SO(4)] was selected as a model for fine atmospheric PM. Treatment of female Sprague-Dawley rats with (NH(4))(2)SO(4) (429 or 215 microg/m(3); 0.3-0.4 microm mass median diameter) or H(2)O(2) (10, 20, or 100 ppb) alone or in combination for 2 h had no major effect on bronchoalveolar lavage fluid cell number or viability or on protein content or lactate dehydrogenase levels, either immediately or 24 h after exposure, relative to air-exposed rats. However, electron microscopy revealed increased numbers of neutrophils in pulmonary capillaries adhered to the vascular endothelium in rats treated with the combination of (NH(4))(2)SO(4) + H(2)O(2). Exposure of rats to (NH(4))(2)SO(4) + H(2)O(2) also resulted in tumor necrosis factor-alpha (TNF-alpha) production by alveolar macrophages. This was observed immediately and 24 h after exposure. Immediately after inhalation of (NH(4))(2)SO(4) + H(2)O(2), a transient increase in production of superoxide anion by alveolar macrophages was observed. In contrast, nitric oxide production by cells from rats exposed to (NH(4))(2)SO(4) + H(2)O(2) or H(2)O(2) alone was decreased, and this persisted for 24 h. Decreases in nitric oxide may be due to superoxide anion-driven formation of peroxynitrite. In this regard, nitrotyrosine, an in vivo marker of peroxynitrite, was detected in lung tissue after exposure of rats to (NH(4))(2)SO(4) + H(2)O(2) or H(2)O(2). We also found that expression of the antioxidant enzyme heme oxygenase-1 by stimulated alveolar macrophages was increased following exposure of rats to (NH(4))(2)SO(4) + H(2)O(2). Taken together, these studies demonstrate that the biological effects of inhaled fine PM are augmented by H(2)O(2). Moreover, tissue injury induced by fine PM may be related to altered production of cytotoxic mediators by alveolar macrophages.

Administration, Inhalation↗
PubMed2001

Minimal amidine structure for inhibition of nitric oxide biosynthesis.

Pharmacological modulation of nitric oxide synthase activity has been achieved using structural analogs of arginine. In the present studies, we demonstrated that the minimal amidine structure required for enzymatic inhibition is formamidine. We found that the production of nitric oxide by primary cultures of rat hepatocytes and several mouse and human cell lines, including RAW 264.7 macrophages, PAM 212 keratinocytes, G8 myoblasts, S180 sarcoma, CX-1 human colon cells, and GH3 rat pituitary cells, was inhibited in a concentration- and time-dependent manner by formamidine. Formamidine was 2- to 6-fold more effective in inhibiting nitric oxide production in cells expressing inducible nitric oxide synthase (NOS2) than in a cell line expressing calcium-dependent neuronal nitric oxide synthase (NOS1). Whereas formamidine had no effect on gamma-interferon-induced expression of nitric oxide synthase protein, its enzymatic activity was blocked. Kinetic analysis revealed that formamidine acts as a simple competitive inhibitor with respect to arginine (K(i) formamidine approximately 800 microM). Using a polarographic microsensor to measure real-time flux of nitric oxide release from RAW 264.7 macrophages, formamidine was found to require 30-90 min to inhibit enzyme activity, suggesting that cellular uptake of the drug may limit its biological activity. Our data indicate that formamidine is an effective inhibitor of nitric oxide production. Furthermore, its low toxicity may make it useful as a potential therapeutic agent in diseases associated with the increased production of nitric oxide.

Amidines↗
PubMed2001

Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice.

Macrophages are known to release a number of different inflammatory mediators with cytotoxic potential. In the present studies we analyzed the role of two macrophage-derived mediators, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide, in liver injury induced by carbon tetrachloride (CCl4). Treatment of mice with CCl4 resulted in a dose- and time-dependent induction of centrilobular hepatic necrosis. This was observed within 12 h with 0.3 ml/kg CCl4 and was correlated with increases in serum transaminase levels. CCl4 administration also caused increases in hepatic TNF-alpha mRNA expression and serum TNF-alpha levels, as well as inducible nitric oxide synthase (NOS II) protein expression in the liver. To study the role of TNF-alpha and nitric oxide in hepatotoxicity, we used knockout mice lacking the gene for the 55-kDa TNF-alpha receptor (TNFR1/p55), the TNF-alpha cytokine, or NOS II. We found that CCl4 was significantly less effective in inducing hepatotoxicity in mice lacking TNFR1/p55 or the TNF-alpha cytokine. In contrast, CCl4-induced liver injury was increased in knockout mice lacking the gene for NOS II. This was associated with an increase in hepatic TNF-alpha mRNA expression and serum TNF-alpha levels. These data suggest that the hepatoprotective effects of nitric oxide in this model may be due in part to inhibition of TNF-alpha.

Acute Disease↗
PubMed2001

Role of macrophages and inflammatory mediators in chemically induced toxicity.

Macrophages are critical cellular effectors of nonspecific host defense. They are also potent secretory cells releasing an array of mediators including proinflammatory and cytotoxic cytokines and growth factors, bioactive lipids, hydrolytic enzymes and reactive oxygen and nitrogen intermediates, each of which has been implicated in tissue injury. The research in our laboratories has focused on analyzing the role of macrophages in chemically induced injury in the lung and the liver. In both these tissues, a localized accumulation of macrophages is observed following toxicant exposure. This is directly correlated with the generation of cytotoxic inflammatory mediators at these sites. Moreover, when macrophage functioning is blocked, pulmonary and hepatic injury induced by toxicants such as ozone or acetaminophen is prevented. These findings provide direct support for our hypothesis that macrophages contribute to tissue injury. Approaches using pharmacologic inhibitors and transgenic animals are currently being used to evaluate the specific macrophage-derived products involved in the pathogenic process. Our results suggest that the extent to which a particular mediator contributes to injury depends on the nature of the toxicant, the target tissue, and quantities of the mediator produced.

Acetaminophen↗
PubMed2001

Nitric oxide and peroxynitrite in ozone-induced lung injury.

One of the hallmarks of the inflammatory response associated with tissue injury is the accumulation of macrophages at sites of damage. These cell types release proinflammatory cytokines and cytotoxic mediators to destroy invading pathogens and initiate wound repair. However, when produced in excessive amounts, these macrophage-derived mediators may actually contribute to tissue injury. This process involves both direct damage to target tissues and amplification of the inflammatory response. One group of macrophage-derived mediators of particular interest are reactive nitrogen intermediates including nitric oxide and peroxynitrite which have been implicated in tissue injury induced by a variety oftoxicants. Our laboratory has been investigating the role of reactive nitrogen intermediates in lung injury induced by oxidants such as ozone. Inhalation of ozone causes epithelial cell damage and Type II cell hyperplasia. This is associated with an accumulation of activated macrophages in the lower lungs which we have demonstrated contribute to toxicity. To analyze the role of macrophage-derived reactive nitrogen intermediates in ozone toxicity, we used transgenic mice lacking the gene for inducible nitric oxide synthase (NOSII). Treatment of wild type control animals with ozone (0.8 ppm) for 3 hr resulted in an increase in bronchoalveolar lavage (BAL) fluid protein reaching a maximum 24-48 hr after exposure. This was correlated with increased expression of NOSII protein and mRNA by alveolar macrophages and increased production of nitric oxide as well as peroxynitrite. Ozone inhalation also resulted in the appearance of nitrotyrosine residues in the lungs, an in vivo marker of peroxynitrite-induced damage. In contrast, in NOSII knockout mice, BAL protein was not increased demonstrating that these mice were protected from ozone-induced epithelial injury. Moreover, alveolar macrophages from the transgenic mice did not produce nitric oxide or peroxynitrite even after ozone inhalation. There was also no evidence for the formation of nitrotyrosine in lung tissue. These data indicate that ozone-induced lung injury is mediated by reactive nitrogen intermediates.

Animals↗
PubMed2001

Pharmacologic therapy of persistent pulmonary hypertension of the newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a potentially life-threatening condition characterized by a failure of pulmonary vascular resistance to decrease adequately during the transition to extrauterine life. Inhaled nitric oxide, a vasodilator that acts selectively on the pulmonary circulation, has revolutionized the treatment of this condition. However, inhaled nitric oxide has not proven effective in all patients, particularly those with congenital diaphragmatic hernias or meconium aspiration syndrome. Furthermore, large clinical trials of inhaled nitric oxide have failed to demonstrate significant differences in mortality between nitric oxide-treated and control infants with PPHN. Other therapeutic approaches to PPHN have been limited by a relative lack of specificity for the pulmonary circulation, and have received much less attention. Pharmacologic approaches, including pulmonary surfactants, prostacyclin, endothelin antagonists, Ca(2+)-channel blockers, magnesium sulfate, and tolazoline, have exhibited varying degrees of efficacy in lowering pulmonary vascular pressures in humans and/or animals. A number of these agents are also effective when used in combination. For example, phosphodiesterase inhibitors have been reported to act synergistically with inhaled nitric oxide. Surfactants also appear to be useful in PPHN, particularly in patients with congenital diaphragmatic hernia, when used in combination with other therapies. Surfactant lavage and other novel therapies may also be effective in combination therapy of meconium aspiration syndrome. Further studies should be directed at defining the optimal therapies in specific clinical settings. Validation of multiple therapeutic modalities for PPHN, including inhaled nitric oxide, will allow for rational, combined vasodilator strategies that are specific for the underlying pathophysiology in each patient.

Anti-Inflammatory Agents↗
PubMed2001

Prooxidant and antioxidant functions of nitric oxide in liver toxicity.

In response to tissue damage and inflammation induced by a variety of xenobiotics including acetaminophen, carbon tetrachloride, ethanol, galactosamine, and endotoxin, as well as disease states such as viral hepatitis, and postischemic and regenerative injury, the liver produces large quantities of nitric oxide. Indeed, nearly all cell types in the liver including hepatocytes, Kupffer cells, stellate cells, and endothelial cells have the capacity to generate nitric oxide. Thus, these cells, as well as infiltrating leukocytes, may indirectly augment tissue injury. In many models of liver damage, nitric oxide and its oxidation products such as peroxynitrite contribute to the injury process by directly damaging the tissue or by initiating additional immunologic reactions that result in damage. In some models, nitric oxide donors or peroxynitrite can mimic the cytotoxic actions of liver toxins. Moreover, agents that prevent the generation of nitric oxide or antioxidants that bind reactive nitrogen intermediates, or knockout mice with reduced capacity to produce nitric oxide, are protected from xenobiotic-induced tissue injury. In contrast, there have been reports that blocking nitric oxide production enhances xenobiotic-induced tissue injury. This has led to the concept that nitric oxide either inactivates proteins critical for xenobiotic-induced tissue injury or acts as an antioxidant, reducing cellular levels of cytotoxic reactive oxygen intermediates. Whether or not nitric oxide or secondary oxidants generated from nitric oxide act as mediators of tissue injury or protect against toxicity is likely to depend on the precise targets of these reactive nitrogen intermediates, as well as levels of superoxide anion present and the extent to which tissue injury is mediated by reactive oxygen intermediates. In addition, as toxicity is a complex process involving a variety of cell types and many soluble mediators, the contribution of each of these factors must be taken into account when considering the role of nitric oxide as a determinant of tissue injury.

Animals↗
PubMed2001

The toxicology of inhaled nitric oxide.

Inhaled nitric oxide is a targeted pulmonary vasodilator that improves clinical outcomes for newborn patients with persistent pulmonary hypertension of the newborn, and may be effective in treating some premature patients with acute respiratory distress syndrome or lung disease of prematurity. Nitric oxide is now recognized as playing an important role in the regulation of diverse physiological processes. However, the pharmacological properties of inhaled nitric oxide are not easy to separate from its toxicological effects. For example, the intended effect of inhaled nitric oxide, vasodilation in the lung, is mediated, in part, by increased cellular cyclic GMP (cGMP). However, increased cGMP can also interfere with normal cellular proliferation. Nitric oxide has also been shown to cause DNA strand breaks and/or base alterations that are potentially mutagenic. Inhaled nitric oxide can rapidly react with oxygen in the lung to form nitrogen dioxide, which is a potent pulmonary irritant. Nitric oxide also reacts with superoxide anion to form peroxynitrite, a cytotoxic oxidant that can interfere with surfactant functioning. The overall effect of inhaled nitric oxide in potentiating or attenuating inflammation and oxidative damage in diseased lung is dependent on the dose administered. Furthermore, despite rapid inactivation by circulating hemoglobin, inhaled nitric oxide exerts effects outside the lung, including blocking platelet aggregation, causing methemoglobinemia, and possibly inducing extrapulmonary vasodilation. The toxicology of inhaled nitric oxide is not completely understood and must be considered in the design of protocols for its safe and effective clinical use.

Animals↗
PubMed2001

Functional heterogeneity in liver and lung macrophages.

Although initially considered merely "scavenger cells" that participate in immunologic responses only after B and T lymphocytes have performed their biological tasks, more recent evidence suggests that macrophages play a key role in host defense as well as in the maintenance of normal tissue structure and function. For macrophages to perform their biological functions, they must be activated. This involves up-regulation of an array of signaling pathways resulting in altered gene expression and increased biochemical and functional activity. Macrophages have been identified in almost all tissues of the body. However, the basal activity of these cells, as well as their ability to respond to inflammatory mediators, varies considerably with their location. In addition, even within a particular tissue, there is evidence of macrophage heterogeneity. The largest populations of macrophages in the body are located in the liver and lung. Because of the unique attributes of these tissues, hepatic and pulmonary macrophages play essential roles not only in nonspecific host defense but also in the homeostatic responses of these tissues. In this review, the functional and biochemical activities of macrophages localized in the liver and lungs are compared. Evidence suggests that these represent distinct cell populations with unique functions and responsiveness to inflammatory agents.

Animals↗
PubMed2001

Mechanisms underlying reduced responsiveness of neonatal neutrophils to distinct chemoattractants.

Potential mechanisms underlying impaired chemotactic responsiveness of neonatal neutrophils were investigated. Two distinct chemoattractants were compared: bacterially derived N-formyl-methionyl-leucyl-phenylalanine (fMLP) and a unique chemotactic monoclonal antibody, designated DL1.2, which binds to a neutrophil antigen with an apparent molecular mass of 120 kDa. Chemotaxis of neutrophils toward fMLP, as well as DL1.2, was reduced in neonates when compared with adult cells. This did not appear to be a result of decreased fMLP receptor or DL1.2 antigen expression by neonatal neutrophils. fMLP, but not DL1.2, induced a rapid increase in intracellular calcium in adult and neonatal cells, which reached a maximum within 30 s. The calcium response of cells from neonates to fMLP was reduced when compared with adult cells, and an unresponsive subpopulation of neonatal neutrophils was identified. NF-kappaB nuclear binding activity induced by fMLP and DL1.2, as well as expression of the p65 NF-kappaB subunit and IkappaB-alpha, was also significantly reduced in neonatal cells, when compared with adult cells. In contrast, although fMLP, but not DL1.2, activated p42/44 and p38 mitogen-activated protein (MAP) kinases in neutrophils, no differences were observed between adults and neonates. Chemotaxis of adult and neonatal neutrophils toward fMLP and DL1.2 was also blocked to a similar extent by inhibitors of phosphatidylinositol 3-kinase, as well as an inhibitor of NF-kappaB. These findings indicate that reduced chemotactic responsiveness in neonatal neutrophils is a result of, at least in part, aberrations in chemoattractant-induced signaling. However, the biochemical pathways mediating this defect appear to be related to the specific chemoattractant.

Adult↗
PubMed2000

Characterization of the inflammatory response to biomaterials using a rodent air pouch model.

Using a rodent air pouch, the inflammatory responses to biomaterials with distinct physical properties and chemical compositions were compared. The polymers examined were expanded poly(tetrafluoroethylene) (ePTFE), silicone, low-density polyethylene (LDPE), poly(L-lactic acid) (PLLA), poly(desaminotyrosyl-tyrosine ethyl carbonate) [poly(DTE carbonate)], and poly(desaminotyrosyl-tyrosine benzyl carbonate) [poly(DTBzl carbonate)]. We found that implantation of disks (4.5-4.8 mm) of these materials into rodent air pouches for 2 days had no effect on the number or type of cells recovered relative to sham controls. With each of the materials, macrophages were the predominant cell type identified (60-75%), followed by granulocytes (20-25%) and lymphocytes (10%). Implantation of poly(DTE carbonate), ePTFE, LDPE, or poly(DTBzl carbonate) into the pouches for 2 days caused an increase in release of superoxide anion by the pouch cells. Cells from pouches containing poly(DTE carbonate) also released more hydrogen peroxide and were more phagocytic. In contrast, PLLA and silicone had no effect on the functional activity of cells recovered from the pouches. Prolonging the implantation time of poly(DTE carbonate) or PLLA to 7 days did not alter the number or type of cells isolated from the pouches. However, cells from pouches containing poly(DTE carbonate) for 7 days continued to produce increased quantities of superoxide anion relative to sham control pouch cells. These results suggest that the air pouch model is a highly sensitive method and therefore useful for evaluating the functional responses of inflammatory cells to biomaterials.

Animals↗
PubMed2000

An exposure system to study the effects of water-soluble gases on PM-induced toxicity.

An aerosol generation and exposure system to evaluate the role of water-soluble gases in particulate matter (PM)-induced injury was designed, built, and validated by generating test atmospheres to study the role of hydrogen peroxide in PM-induced toxicity. In this system, particle number concentration, size distribution, hydrogen peroxide concentration, and water concentration can all be varied. An ammonium sulfate aerosol with mass median diameter 0.46 +/- 0.01 microm was used as a model atmospheric aerosol because ammonium sulfate is a major component of the fine aerosol, and the water uptake of ammonium sulfate aerosol is well characterized. The following four test atmospheres were generated: (1) ammonium sulfate aerosol, (2) an aerosol containing hydrogen peroxide and ammonium sulfate, (3) vapor-phase hydrogen peroxide, and (4) particle-free air. All test atmospheres were maintained at a relative humidity of 85%. Particle size distribution, number concentration, total hydrogen peroxide concentration, temperature, and relative humidity were measured continuously in the exposure chamber. The gas-particle partitioning of hydrogen peroxide was calculated using total hydrogen peroxide concentration, the Henry's law constant for hydrogen peroxide in water, and aerosol water content. We found that the aerosol generation system produced stable concentrations throughout the 2-hour exposures.

Aerosols↗
PubMed2000

Functional heterogeneity of rat hepatic and alveolar macrophages: effects of chronic ethanol administration.

Chronic ethanol consumption is associated with increased incidence of hepatic and pulmonary infections. To determine if this is correlated with altered macrophage activity, we analyzed the functional properties of cells isolated sequentially from the liver and lung of rats fed a liquid diet containing ethanol (35% of calories) or malto-dextrin control for 9-12 weeks. Hepatic and alveolar macrophages from control animals were found to exhibit distinct morphologic and functional properties. Thus, hepatic macrophages were highly vacuolated and appeared larger and more irregular in shape than alveolar macrophages. These cells also displayed greater phagocytic activity and random migration. In contrast, lung macrophages produced more superoxide anion and nitric oxide, and exhibited enhanced chemotactic activity toward the complement fragment C5a. Whereas administration of ethanol to rats for 9-12 weeks resulted in decreased chemotaxis and superoxide anion production by alveolar macrophages, cell adhesion molecule expression was reduced in hepatic macrophages. Nitric oxide production and inducible nitric oxide synthase protein expression were decreased in both macrophage populations. These effects were not observed after 3-6 weeks of ethanol administration to rats. Our results suggest that changes in macrophage functioning may play a role in decreased host defense following chronic ethanol exposure.

Animals↗
PubMed1999

Inhibition of macrophages with gadolinium chloride alters intercellular adhesion molecule-1 expression in the liver during acute endotoxemia in rats.

Cell adhesion molecules are important for localized accumulation of phagocytes at sites of tissue damage. In the present studies, we analyzed the effects of blocking hepatic macrophages on expression of beta2 integrins and intercellular adhesion molecule-1 (ICAM-1) adhesion molecules on liver cells during acute endotoxemia. Flow cytometric analysis revealed distinct subpopulations of macrophages from control animals that varied on the basis of their size and density. In contrast, hepatocytes and endothelial cells were relatively homogeneous. Treatment of rats with endotoxin (5 mg/kg, intravenously) resulted in a time-dependent increase in the percentage of small, dense macrophages and a progressive loss of larger, less-dense cells. In contrast, no major effects were observed on the physical properties of hepatocytes or endothelial cells. ICAM-1 was found to be constitutively expressed on endothelial cells and hepatocytes, as well as on macrophages. Induction of acute endotoxemia resulted in a time-dependent increase in ICAM-1 expression on hepatocytes, which was observed within 3 hours and reached a maximum after 24 hours. An increase in ICAM-1 expression was also observed on endothelial cells and on macrophages at 3 hours, followed by a decrease at 24 to 48 hours. Macrophages and endothelial cells also constitutively expressed beta2 integrins. Induction of acute endotoxemia had no effect on beta2 integrin expression by these cells. Pretreatment of rats with gadolinium chloride (GdCl3), a macrophage inhibitor known to block endotoxin-induced liver injury, abrogated the effects of endotoxin on ICAM-1 expression by hepatocytes and macrophages. In contrast, ICAM-1 expression on endothelial cells increased. Interestingly, treatment of rats with GdCl3 alone resulted in a marked increase in expression of ICAM-1 on endothelial cells and hepatocytes, and of beta2 integrins on macrophages and endothelial cells. Taken together, these data suggest that ICAM-1 is involved in mediating macrophage adherence and accumulation in the liver during endotoxemia. Furthermore, macrophages appear to regulate expression of this cell adhesion molecule on parenchymal cells.

Acute Disease↗
PubMed1999

Nitric oxide in the lung: therapeutic and cellular mechanisms of action.

Nitric oxide is produced by many cell types in the lung and plays an important physiologic role in the regulation of pulmonary vasomotor tone by several known mechanisms. Nitric oxide stimulates soluble guanylyl cyclase, resulting in increased levels of cyclic GMP in lung smooth muscle cells. The gating of K+ and Ca2+ channels by cyclic GMP binding is thought to play a role in nitric oxide-mediated vasodilation. Nitric oxide may also regulate pulmonary vasodilation by direct activation of K+ channels or by modulating the expression and activity of angiotensin II receptors. Administration of nitric oxide by inhalation has been shown to acutely improve hypoxemia associated with pulmonary hypertension in humans and animals. This is presumably due to its ability to induce pulmonary vasodilation. Inhaled nitric oxide improves oxygenation and reduces the need for extracorporeal membrane oxygenation in term and near-term infants with persistent pulmonary hypertension. However, long-term benefits to these infants have been difficult to demonstrate. In other pathologic conditions, such as prematurity and acute respiratory distress syndrome, short-term benefits have not been shown conclusively to outweigh potential toxicities. For example, high-dose inhaled nitric oxide decreases surfactant function in the lung. Inhaled nitric oxide also acts as a pulmonary irritant, causing priming of lung macrophages and oxidative damage to lung epithelial cells. Conversely, protective effects of nitric oxide have been described in a number of pathological states, including hyperoxic and ischemia/reperfusion injury. Nitric oxide has also been reported to protect against oxidative damage induced by other reactive intermediates, including superoxide anion and hydroxyl radical. The dose and timing of nitric oxide administration needs to be ascertained in clinical trials before recommendations can be made regarding its optimal use in patients.

Administration, Inhalation↗
PubMed1998

Role of inflammatory cytokines and nitric oxide in hepatic and pulmonary toxicity.

Exposure of humans and experimental animals to inhaled irritants such as ozone, induces an acute inflammatory response and lung injury. We hypothesize that macrophage-derived inflammatory cytokines and cytotoxic mediators contribute to the pathogenic process. Treatment of rats with ozone (2 ppm, 3 h) results in damage to the alveolar epithelium and increased protein in lung lavage fluid. This is associated with an increase in the number of macrophages in the lung. We found that these cells are activated to release the proinflammatory cytokine tumor necrosis factor-alpha (TNF alpha) which has been implicated in tissue injury. Following ozone inhalation, alveolar macrophages also produce increased amounts of the cytotoxic mediator, nitric oxide. This response is time-dependent and correlated with expression of inducible nitric oxide synthase (NOS II) protein and mRNA. Inhibition of macrophages with gadolinium chloride abrogates ozone-induced inflammation, mediator production and tissue injury. These data demonstrate, that macrophages and mediators they release contribute to irritant-induced lung injury. Ozone inhalation also caused alterations in the liver, including increased nitric oxide production and protein synthesis suggesting that ozone induces an acute phase response. We speculate that this is mediated by cytokines such as TNF alpha produced by alveolar macrophages. In this regard we noted increased expression of TNF alpha in both lung and liver tissue. Thus cytokines produced locally by macrophages following toxicant exposure may exert pathophysiologic effects outside the target organ.

Animals↗