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PubMed1988

Toxicokinetics and bioavailability of paraquat in rats following different routes of administration.

The toxicokinetics and bioavailability of [14C]paraquat were examined in rats which had received a single dose (11.6 micrograms/kg) of the herbicide by the iv, intragastric, dermal or pulmonary route. In the pulmonary route studies, rats were exposed to an aqueous solution or liquid aerosols of [14C]paraquat through a tracheal cannula or [14C]paraquat aerosols in a nose-only inhalation chamber. After intratracheal, intragastric, and dermal administration of [14C]paraquat to the rat, the average bioavailabilities were 0.45 +/- 0.22, 0.12 +/- 0.03, and 0.038 +/- 0.027, which corresponded to 20.3 nmol, 5.4 nmol and 1.7 nmol of [14C]paraquat, respectively. Since the dose administered to the rat in the [14C]paraquat aerosol studies was unknown, the bioavailability for this exposure route could not be determined. However, about 27.5 nmol of [14C]paraquat was observed into the systemic circulation of the rat after inhaling [14C]paraquat aerosols through a tracheal cannula. [14C]paraquat administered to the rat iv was eliminated from the blood with a half-life of about 68 min. Urine and feces were the major excretion routes. The radioactivity absorbed into the systemic circulation of the rat was approximately equal to that excreted in the urine; about 23.8 nmol, 8.5 nmol and 1.5 nmol of [14C]paraquat were recovered from the urine of the rat after inhalation of [14C]paraquat aerosols in a nose-only exposure chamber, intragastric injection and dermal absorption of [14C]paraquat, respectively. Tissue distribution studies showed that the bulk of the [14C]paraquat administered to the rat by the inhalation and dermal routes remained at the sites of administration.

Administration, Cutaneous↗
PubMed2000

Gamma delta-T cells are critical for survival and early proinflammatory cytokine gene expression during murine Klebsiella pneumonia.

Although cells of the innate inflammatory response, such as macrophages and neutrophils, have been extensively studied in the arena of Gram-negative bacterial pneumonia, a role for T cells remains unknown. To study the role of specific T cell populations in bacterial pneumonia, mice deleted of their TCR beta- and/or delta-chain were intratracheally inoculated with Klebsiella pneumoniae. Gamma delta T cell knockout mice displayed increased mortality at both early and late time points. In contrast, mice specifically lacking only alpha beta-T cells were no more susceptible than wild-type mice. Pulmonary bacterial clearance in gamma delta-T cell knockout mice was unimpaired. Interestingly, these mice displayed increased peripheral blood dissemination. Rapid up-regulation of IFN-gamma and TNF-alpha gene expression, critical during bacterial infections, was markedly impaired in lung and liver tissue from gamma delta-T cell-deficient mice 24 h postinfection. The increased peripheral blood bacterial dissemination correlated with impaired hepatic bacterial clearance following pulmonary infection and increased hepatic injury as measured by plasma aspartate aminotransferase activity. Combined, these data suggest that mice lacking gamma delta-T cells have an impaired ability to resolve disseminated bacterial infections subsequent to the initial pulmonary infection. These data indicate that gamma delta-T cells comprise a critical component of the acute inflammatory response toward extracellular Gram-negative bacterial infections and are vital for the early production of the proinflammatory cytokines IFN-gamma and TNF-alpha.

Animals↗
PubMed1998

Silica-induced pulmonary inflammation in rats: activation of NF-kappa B and its suppression by dexamethasone.

The goal of this study was to examine the relationship of the transcriptional regulatory factor nuclear factor-kappaB (NF-kappa B) to the early inflammatory events involved with silica exposure. Male F-344 rats received an intratracheal (i.t.) instillation of silica (100 mg/kg in a volume of 1 ml/kg) of saline. At 1, 3, 6, and 18 h postinstillation, and the rats were sacrificed and underwent bronchoalveolar lavage (BAL) for functional analysis of inflammation. Beginning at 1 h postinstillation, the silica-instilled (Si) rats displayed significant increases in neutrophils in BAL fluid compared to the saline controls. BAL cells from the Si group displayed a significant increase in luminol-dependent chemiluminescence (LDCL) compared to the controls. NF-kappa B activation was measurable at 3 h postinstillation, and this activation continued throughout the 18-h time course. Treatment with dexamethasone (5 mg/kg) at -3 h prior to silica instillation, at the time of instillation (0 h), and +1.5 h postinstillation resulted in both a reduction in NF-kappa B expression (by 70%) at 3 h postinstillation and corresponding reductions in LDCL, BAL cell count, and BAL neutrophils. These results show that activation of NF-kappa B is associated with silica-induced pulmonary inflammation, and the inhibition of its activation correlates temporally with suppression of inflammation.

Animals↗
PubMed1993

Changes in pulmonary hemodynamics during normoxia and hypoxia in awake rats treated with intratracheal bleomycin.

Pulmonary hemodynamics of bleomycin-induced interstitial fibrosis model (group-BLM, n = 10) and saline-treated control (group-C, n = 12) were studied in awake rats. Four weeks before hemodynamic study, bleomycin sulfate and normal saline was intratracheally instilled to the group-BLM and the group-C, respectively. Pulmonary artery and abdominal aortic catheters were indwelled two days before the hemodynamic study. In room air, mean pulmonary artery pressure (Ppa) was significantly higher and systemic artery pressure was significantly lower in group-BLM than in group-C; Ppa = 21 +/- 1 cmH2O (mean +/- S.E.) for group-C and 38 +/- 4 cmH2O for group-BLM. Cardiac output did not differ among the groups. Mean pulmonary vascular resistance (PVR) of group-BLM was double that of group-C. Right ventricle was hypertrophic in group-BLM. When exposed to 10% O2, PVR of group-C significantly rose, whereas PVR of group-BLM showed very little increase, showing attenuation of the hypoxic pulmonary vasoconstriction (HPV). Magnitude of the HPV was inversely related to Ppa during air breathing. We conclude that notable pulmonary hypertension and right ventricular hypertrophy occur, and HPV is blunted four weeks after bleomycin instillation, at the most severe period of this lung fibrosis model. We speculate that the high intravascular pressure partly contributed to the blunted HPV in bleomycin-treated group.

Animals↗
PubMed1987

Intratracheal suctioning in sick preterm infants: prevention of intracranial hypertension and cerebral hypoperfusion by muscle paralysis.

In a prospective nonrandomized study, using each baby as his or her own control, we compared intracranial pressure (anterior fontanel pressure as measured with the Digilab pneumotonometer), cerebral perfusion pressure, BP, heart rate, transcutaneous Po2, and transcutaneous Pco2 before, during, and after endotracheal suctioning, with and without muscle paralysis, in 28 critically ill preterm infants with respiratory distress syndrome. With suctioning, there was a small but significant increase in intracranial pressure in paralyzed patients (from 13.7 [mean] +/- 4.4 mm Hg [SD] to 15.8 +/- 5.2 mm Hg) but a significantly larger (P less than .001) increase when they were not paralyzed (from 12.5 +/- 3.6 to 28.5 +/- 8.3 mm Hg). Suctioning led to a slight increase in BP with (from 45.3 +/- 9.1 to 48.0 +/- 8.7 mm Hg) and without muscle paralysis (from 45.1 +/- 9.4 to 50.0 +/- 11.7 mm Hg); but there was no significant difference between the two groups. The cerebral perfusion pressure in paralyzed infants did not show any significant change before, during, and after suctioning (31.5 +/- 9.1 mm Hg before v 32.0 +/- 8.7 mm Hg during suctioning), but without muscle paralysis cerebral perfusion pressure decreased (P less than .001) from 32.8 +/- 9.7 to 21.3 +/- 13.1 mm Hg. Suctioning induced a slight decrease in mean heart rate and transcutaneous Po2, but pancuronium did not alter these changes. There was no statistical difference in transcutaneous Pco2 before, during, and after suctioning with and without muscle paralysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Gas Monitoring, Transcutaneous↗
PubMed1996

Role of intercellular adhesion molecule-1 in glucan-induced pulmonary granulomatosis in the rat.

Glucan-induced pulmonary granulomatous vasculitis in the rat mimics several human lung diseases (e.g., Wegener's granulomatosis, intravenous talcosis). We sought to clarify the role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of glucan-induced granulomatous vasculitis. Immunohistochemical analysis of lung sections from rats with florid vasculitis (48 hours) revealed marked alveolar septal and lesional expression of ICAM-1. An ex vivo binding analysis with isotope-labeled antibodies and lung sections taken at various times up to 48 hours after glucan infusion revealed a progressive increase in whole-lung ICAM-1 expression. In vivo measurements of vascular wall-associated ICAM-1 expression revealed an earlier rise that began less than 6 hours after glucan infusion, peaked at 24 to 48 hours, and then declined to near baseline during the ensuing 24 to 96 hours. To assess whether ICAM-1 expression both within blood vessel walls and within lesions per se is important in granuloma development, we carried out in vivo neutralization experiments with several different routes of administration of antibody to ICAM-1. Monoclonal antibody to rat ICAM-1 was either infused intravenously at time 0 (when glucan was infused), infused intravenously at time 0 and after 24 hours, instilled only intratracheally 24 hours after glucan infusion, or given both intravenously (time = 0 and 24 hours) and intratracheally (time = 24 hours). Infusions of monoclonal antibody to rat ICAM-1 resulted in dose-dependent reductions in mean granuloma number and cross-sectional area. Intrapulmonary instillation of antibody to rat ICAM-1 (via tracheostomy 24 hours after glucan infusion) resulted in a modest reduction in mean granuloma number and cross-sectional area. When antibody to ICAM-1 was both infused and instilled via the trachea, we found an additive reduction in mean granuloma size and number. There was a 12-fold increase in adhesion of ED-1-positive peripheral blood mononuclear cells (monocytes) to granuloma-bearing frozen lung sections prepared 48 hours after glucan infusion. Moreover, 73% of the additional adherent monocytes were bound specifically to granulomas per se. The increase in ex vivo monocyte binding to lung sections prepared at 48 hours was reduced 62% when sections were incubated with monoclonal antibody to ICAM-1. Taken together, these data indicate that ICAM-1 expression in evolving glucan-induced granulomatous vasculitis occurs first within blood vessel walls and then within lesional cells per se. The in vivo blocking studies suggest that ICAM-1 expression in both anatomic sites is important in granuloma development.

Animals↗
PubMed2003

Oxidative DNA damage in vitamin C-supplemented guinea pigs after intratracheal instillation of diesel exhaust particles.

The health effects of diesel exhaust particles (DEP) are thought to involve oxidative damage. We have investigated the effect of intratracheal DEP instillation to guinea pigs in three groups of 12 animals each given 0, 0.7, or 2.1 mg. Five days later guinea pigs exposed to DEP had increased levels of oxidized amino acids (gamma-glutamyl semialdehyde), DNA strand breaks, and 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in the lung. Bulky DNA ad- ducts were not significantly elevated in the lung. The antioxidant enzyme activity of glutathione reductase was increased in the lung of DEP-exposed guinea pigs, whereas glutathione peroxidase and superoxide dismutase enzyme activities were unaltered. There was no difference in DNA strand breaks in lymphocytes or urinary excretion of 8-oxodG at the two doses tested. Protein oxidations in plasma and in erythrocytes were not altered by DEP exposure. The concentrations of ascorbate in liver, lung, and plasma were unaltered by the DEP exposure. The results indicate that in guinea pigs DEP causes oxidative DNA damage rather than bulky DNA adducts in the lung. Guinea pigs, which are similar to humans with respect to vitamin C metabolism, may serve as a new model for the study of oxidative damage induced by particulate matter.

Animals↗
PubMed1992

The pharmacokinetics of pulmonary-delivered insulin: a comparison of intratracheal and aerosol administration to the rabbit.

The pulmonary deposition and pharmacokinetics of insulin, administered via an endotracheal tube as an aerosol and instillate, in formulations containing either 113mIn-DTPA or 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in four male New Zealand White rabbits. Using a randomized crossover design, the pharmacokinetics of intravenous insulin were also characterized. Recovery of immunoreactive insulin after nebulization was greater than 90%, indicating that the aerosolisation procedure did not cause appreciable insulin degradation. Gamma scintigraphy demonstrated that the penetration index (peripheral:central deposition) for the aerosolized formulation (1.52) was much greater than that for the instillate (0.32). Gamma scintigraphy also allowed exact quantification of the dose deposited after aerosol administration and thus permitted accurate determination of bioavailabilities. The bioavailable fraction for aerosolized insulin was 10-fold greater than for instilled insulin (57.2 vs 5.6%). Mucociliary clearance was likely to be greater for the instillate since it showed a preferential central deposition; this may account for the lower bioavailability. Insulin pharmacokinetics from both pulmonary formulations were absorption rate limited, resulting in postpeak half-lives which were approximately 20-fold greater than the intravenous elimination half-life (3 min). The apparent absorption rate constants resulting from instillation and aerosolisation were statistically equivalent (0.015 and 0.011 min-1, respectively). Mucociliary clearance of insulin would result in an overestimation of the true absorption rate constant; hence if mucociliary transport were greater for the instillate, then the true airways to blood transfer rate constant will be higher for the aerosolized formulation.

Aerosols↗
PubMed1997

Anti-T cell receptor antibody prolongs transgene expression and reduces lung inflammation after adenovirus-mediated gene transfer.

Replication-deficient delta E1a-E3 adenovirus mediates efficient gene transfer to the mouse lung; however it induces a host immune response mediated, in part, by T cells. This immune response is associated with loss of transgene expression. Monoclonal antibodies (mAb) against the T cell receptor (TCR) complex can inhibit both CD4+ and CD8+ T cell responses in vivo and are the most potent anti-T cell agents in clinical use. To determine whether such mAbs can be used to prolong adenovirus-mediated transgene expression, the vector Av1Luc1 (delta E1a-E3 recombinant adenovirus encoding the firefly luciferase gene) was administered intratracheally to C57BL/6 mice on day 0. Three days prior to adenovirus administration (day -3), mice were treated with a single i.p. injection of the anti-TCR mAb H57. Controls received phosphate-buffered saline. Animals were sacrificed on days 3, 14, 28, and 56 and lungs were assessed for transgene expression and histopathology. Luciferase activity decreased markedly in the controls by day 14, but was maintained at high levels in animals receiving anti-TCR mAb. A mild, focal, predominantly neutrophilic inflammation was observed in the alveoli of all mice 3 days after virus administration. In PBS-treated controls, this inflammation progressed to a moderate to severe multifocal, perivascular and peribronchiolar lymphoid infiltration at 14 days. B cells and T cells were present in approximately equal numbers, with CD4+ T cells predominating over CD8+ T cells by 3- to 28-fold. Treatment with H57 resulted in near-complete prevention of the lymphocytic inflammatory infiltrate and increased luciferase activity throughout the 56-day study period, in association with TCR modulation and T cell depletion. Thus, anti-TCR mAb decreases inflammation and prolongs gene expression following adenovirus-mediated gene transfer.

Adenoviridae↗
PubMed2001

The allergen-induced airway hyperresponsiveness in a human-mouse chimera model of asthma is T cell and IL-4 and IL-5 dependent.

The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-gamma after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype.

Allergens↗
PubMed2002

Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia.

Leptin is an adipocyte-derived hormone that is secreted in correlation with total body lipid stores. Serum leptin levels are lowered by the loss of body fat mass that would accompany starvation and malnutrition. Recently, leptin has been shown to modulate innate immune responses such as macrophage phagocytosis and cytokine synthesis in vitro. To determine whether leptin plays a role in the innate host response against Gram-negative pneumonia in vivo, we compared the responses of leptin-deficient and wild-type mice following an intratracheal challenge of Klebsiella pneumoniae. Following K. pneumoniae administration, we observed increased leptin levels in serum, bronchoalveolar lavage fluid, and whole lung homogenates. In a survival study, leptin-deficient mice, as compared with wild-type mice, exhibited increased mortality following K. pneumoniae administration. The increased susceptibility to K. pneumoniae in the leptin-deficient mice was associated with reduced bacterial clearance and defective alveolar macrophage phagocytosis in vitro. The exogenous addition of very high levels of leptin (500 ng/ml) restored the defect in alveolar macrophage phagocytosis of K. pneumoniae in vitro. While there were no differences between wild-type and leptin-deficient mice in lung homogenate cytokines TNF-alpha, IL-12, or macrophage-inflammatory protein-2 after K. pneumoniae administration, leukotriene synthesis in lung macrophages from leptin-deficient mice was reduced. Leukotriene production was restored by the addition of exogenous leptin (500 ng/ml) to macrophages in vitro. This study demonstrates for the first time that leptin-deficient mice display impaired host defense in bacterial pneumonia that may be due to a defect in alveolar macrophage phagocytosis and leukotriene synthesis.

Animals↗
PubMed2006

Effects of single intratracheal exposure to chlorhexidine gluconate on the rat lung.

Chlorhexidine gluconate (CHX) is an antiseptic that has been widely used for disinfection of cutaneous wound and gingivae. Recently, a patient who inhaled CHX solution died from acute respiratory distress syndrome (ARDS). Although it is highly possible that direct pulmonary damage might be the cause of ARDS, there is no preclinical information about the pulmonary toxicity of CHX. In the current study, the acute direct action of CHX to the lung was evaluated in rats. We successfully exposed the left but not the right lung either to CHX at concentrations of 1%, 0.1%, and 0.01% or to saline using a curved-tip administration tube. At the higher concentrations of CHX (0.1% and 1%), severe congestion to the alveoli and capillaries and perivascular and intra-alveolar hemorrhages were observed 1 day after exposure. Aniline blue-stained collagen fibers with an infiltration of inflammatory cells were present 7 days after exposure. The fibrotic changes and intra-alveolar inflammatory cells had decreased but were still observed sporadically 28 and 84 days after exposure. These detrimental effects were more severe at 1% than at 0.1% CHX. No remarkable effect was observed after exposures to 0.01% CHX and saline. We were able to evaluate the time-course changes in the pulmonary toxicity of CHX by exposures limited to the left lung. It is highly possible that CHX at a concentration of more than 0.1% might directly induce ARDS when aspirated and reaching to the alveoli.

Animals↗
PubMed1998

Freshly generated stainless steel welding fume induces greater lung inflammation in rats as compared to aged fume.

It has been previously reported that both short- and long-lived reactive oxygen species (ROS) are present on the surface of freshly generated fumes. The objective of this study was to determine if freshly formed welding fume induces greater lung inflammation and injury in rats due to the presence of reactive oxygen species than aged welding fume. Fume was collected during gas metal arc welding using a stainless steel consumable electrode and found to be of respirable size with a mean diameter of 0.77 microm +/- 0.48. Male CD/VAF rats were dosed intratracheally with the welding fume 30 min (fresh) and 1 and 7 days (aged) after fume collection at a dose of 1.0 mg/100 g b wt. Bronchoalveolar lavage (BAL) was performed 24 h post-instillation. Lung injury and inflammation were assessed by measuring the concentration of neutrophils, albumin, lactate dehydrogenase (LDH), and glucosaminidase (GLU) in the recovered BAL fluid. More neutrophils and enhanced GLU activity were observed for the 'fresh' group as compared to both 'aged' groups (P < 0.05). Slight, but not significant, elevations were seen in albumin content and LDH activity for the 'fresh' group as compared to the 'aged' groups. No significant differences were observed for any of the parameters when fume aged for 1 and 7 days were compared. When the 'fresh' and 'aged' fumes (12.5, 25, and 50 microg/ml) were suspended in dichlorofluorescin (15 microM), a probe which becomes fluorescent when oxidized, the concentration-dependent increases in fluorescence were greater for the 'fresh' fume versus the 'aged' fumes. We have demonstrated that freshly generated stainless steel welding fume induces greater lung inflammation than 'aged' fume. This is likely due to a higher concentration of ROS on fresh fume surfaces.

Air Pollutants, Occupational↗
PubMed2004

Pulmonary toxicity of polyvinyl chloride particles after a single intratracheal instillation in rats. Time course and comparison with silica.

Our previous in vitro studies indicated that emulsion polyvinyl chloride (PVC) particles (PVC-E3), with a mean diameter of 2 microm, exhibited a moderate toxicity in different pulmonary cell cultures. The in vitro cytotoxicity and pro-inflammatory potential of PVC-E3 particles were reduced when the additives had been "washed off" (PVC-W3), indicating that PVC-particle associated toxicity is probably related to the residual additives. In the present study, male Wistar rats (230 +/- 18 g) received a single intratracheal instillation of vehicle, crystalline silica particles [Min-U-Sil, 10 mg/kg body weight (BW)], PVC-E3 (10 or 50 mg/kg BW), or PVC-W3 (10 or 50 mg/kg BW). After 2, 7, 28, or 90 days, the rats were sacrificed (n = 6) and pulmonary injury and inflammation were determined by measuring lung weight, lactate dehydrogenase (LDH) activity and protein concentrations in bronchoalveolar lavage fluid (BALF), differential BALF cell count, and histopathology. Silica exposure resulted in pulmonary inflammation and damage at all time points with a progressive deterioration. Exposure to high concentrations of PVC particles caused pulmonary inflammation and damage, which were similar to the silica-exposed group at 2 days, but at 90 days, most parameters had returned to the control level, except for minor histopathological lesions. PVC-E3 did not induce more damage than PVC-W3. Two days after exposure, PVC-W3 caused less neutrophil but more eosinophil influx than PVC-E3. Although the pulmonary toxicity of both PVC-E3 and PVC-W3 appeared limited, this in vivo study has not confirmed the conclusion from the in vitro toxicity tests that removal of residual additives reduces the toxicity of PVC-E3 particles.

Animals↗
PubMed2003

Protection with antibody to tumor necrosis factor differs with similarly lethal Escherichia coli versus Staphylococcus aureus pneumonia in rats.

BACKGROUND: Differing factors may alter the effects of antibody to tumor necrosis factor (TNF) in infection and sepsis. The authors tested whether bacteria type or treatment route alters antibody to TNF in a rat model of bacterial pneumonia. METHODS: Rats (n = 231) received similarly lethal doses of either intratracheal Escherichia coli or Staphylococcus aureus followed by treatment with either intratracheal or intraperitoneal antibody to TNF or control serum. Animals received antibiotics (cefotiam daily dose, 100 mg/kg) starting 4 h after inoculation and were studied for up to 96 h. RESULTS: Compared with S. aureus, E. coli increased serum TNF and interleukin-6 concentrations, lung lavage TNF concentrations, neutrophil counts, and alveolar-to-arterial oxygen gradients and decreased circulating neutrophils and lymphocytes (P > or = 0.05 for all). Compared with controls, with both bacteria, except for lung lavage TNF concentrations (which decreased with intratracheal but not with intraperitoneal antibody to TNF), treatment route did not alter the effects of antibody to TNF on any parameter (P = not significant for all). Antibody to TNF reduced mortality rates (relative risk of death +/- SEM) with both E. coli (-1.6 +/- 0.6; P = 0.006) and S. aureus (-0.5 +/- 0.04; P = 0.185), but these reductions were greater with E. coli than with S. aureus in a trend approaching statistical significance (P = 0.09). Compared with controls, similarly (P = not significant) with both bacteria, antibody to TNF decreased lung lavage and tissue bacteria concentrations (both P < 0.05) and serum TNF concentration (P < 0.09) and increased circulating neutrophils and lymphocytes (both P < or = 0.01). Compared with S. aureus, with E. coli antibody to TNF decreased alveolar-to-arterial oxygen gradients (P = 0.04) and increased serum interleukin-6 concentrations (P = 0.003). CONCLUSION: Antibody to TNF improved host defense and survival rates with both lethal E. coli and S. aureus pneumonia, but protection was greater with E. coli, where TNF concentrations were higher than with S. aureus. The efficacy of antiinflammatory agents in sepsis may be altered by bacteria type.

Administration, Inhalation↗
PubMed1997

Evaluation of potentially injurious effects of exogenous surfactant lysophospholipids on the alveolar epithelium and pulmonary mechanics.

Although lysophospholipids are normally found in the lung and their presence is connected to the metabolic pathway of surfactant phospholipids, several studies have reported that their intratracheal instillation is able to induce severe alveolar epithelial injury. Since lysophospholipids are normally present in exogenous surfactants as a consequence of the nonenzymatic hydrolysis of parent phospholipids during their production and shelf-life, the aim of this study was to test the potential toxicity of surfactant lysophospholipids in artificially ventilated newborn rabbits in comparison with that of pure lysophosphatidylcholine (Lyso-PC) suspensions. In premature (surfactant-deficient) animals, a commercially available Curosurf batch (0.56 mg Lyso-PC/ml) improved lung-thorax compliance and reduced lactate dehydrogenase (LDH), total protein and hemoglobin contents in bronchoalveolar lavage (BAL) fluid. The same batch submitted to thermal stress in order to increase the Lyso-PC content (10.2 mg Lyso-PC/ml) failed to improve lung mechanics but did not induce any significant change in biochemical markers in BAL fluid. When suspended in saline, pure Lyso-PC had a dramatic and dose-dependent tissue-damaging effect with increased LDH, hemoglobin and protein contents in BAL and a fall in the lungthorax compliance, in both immature and mature (near-term) animals. The lack of toxicity of Lyso-PC in Curosurf might be explained by an interaction with surfactant phospholipids.

Animals↗
PubMed2000

Repeated pulmonary function measurements in rats after intratracheal instillation of a polyamine textile pigment component.

The pulmonary response of Wistar rats to a cumulative dose of 1 mg/kg body weight of a polymeric alpha,omega-diamine was examined using the intratracheal route of administration. Instillation of the test substance was on days 0 and 7 followed by a 3-month postobservation period. Static and dynamic pulmonary function tests, including arterial blood gas determinations, were performed during wk 5, 9, and 13. At all time points, significantly depressed flow-volume curves, reduced quasistatic compliance, and reduced vital capacity were observed. These were associated with increases of residual volume and functional residual capacity in the presence of unremarkable changes of total lung capacity (TLC). One of the most predominant dysfunctions of the lung was a severe maldistribution of ventilation, indicated by the single-breath nitrogen washout test. The carbon monoxide diffusing capacity (DL(CO)), in turn, was only mildly decreased, and differences between treatment and control groups did not reach statistical significance. Assessment of arterial blood gases demonstrated a statistically significantly increased venous admixture with subsequent slight hypoxemia. In summary, the predominant dysfunction appeared to be consistent with an obstructive rather than restrictive lung disease. The functional changes observed may account for the effect on arterial blood gases, suggesting a mismatch of the ventilation-perfusion relationship. Either measurement appear to demonstrate a relative stable dysfunction during the 3-mo postinstillation observation period. Collectively, this study supports the view held that polymeric alpha, omega-diamines appear to be potent pneumotoxicants.

Animals↗
PubMed2001

Suppression of allergic immune responses to house dust mite (HDM) in rats exposed to 2,3,7,8-TCDD.

Exposure to various xenobiotics, including oxidant gases, diesel exhaust, and certain pesticides, has been reported to exacerbate pulmonary allergic hypersensitivity responses. Increased lymphocyte proliferative responses to parasite antigens or increased antibody responses to sheep erythrocyte have also been reported in rats exposed to TCDD before infection or immunization. As a result, these studies were conducted to test the hypothesis that TCDD exposure exacerbates the allergic response to house dust mite antigen. Brown Norway rats were injected, ip, with 0, 1, 10, or 30 microg TCDD/kg 7 days before intratracheal (it) sensitization to semipurified house dust mite allergen (HDM). Fourteen days later, rats were challenged with HDM and immediate bronchospasm was measured. At this time point, plus 2 and 7 days later, inflammatory cells in bronchoalveolar lavage fluid (BALF), HDM-specific IgE levels in serum, and HDM-driven cell proliferation in bronchial lymph nodes and spleen were evaluated. TCDD exposure decreased both immediate bronchoconstriction and specific IgE synthesis after the HDM challenge; 7 days later, HDM-specific IgE responses remained suppressed. Total serum IgE levels were similar in all groups. HDM challenge alone significantly increased cellular and biochemical indicators of lung injury, both of which were suppressed by TCDD exposure. The proliferative response of lymph node cells, but not of spleen cells, to HDM was also suppressed at the highest TCDD dose, although the splenic response to Concanavalin A was elevated. It appears that early events in the response to HDM are affected by TCDD exposure, since message for IL5 was dramatically reduced 2 days after sensitization, but not after challenge. We therefore conclude that TCDD exposure suppressed, rather than enhanced the development of allergic immune responses and the expression of immune-mediated lung disease.

Allergens↗