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Biomedical subjects

S N Giri

Publications and source records attributed to S N Giri.

At least 19 recordsLinked to original sources
PubMed2004

Pharmacokinetics of orally administered pirfenidone in male and female beagles.

Pirfenidone, a promising antifibrotic agent, was administered orally to dogs at 0, 40, 140, and 400 mg/kg/day. Serum was collected for pirfenidone assay at 0, 26 and 39 weeks of treatment. From the pirfenidone concentrations, pharmacokinetic parameters were determined for each dog at each treatment interval. The only significant differences because of gender were for concentration maxima. Unsurprisingly, there were many significant differences because of dose in concentration maximum and area under curve (AUC), and significant, positive linear correlations of both parameters with dose. There were few significant differences in time of maximal concentration and no correlation with dose. The mean +/- SE clearances were 1.99 +/- 0.13, 1.64 +/- 0.13 and 1.78 +/- 0.14 L/h/kg for doses of 40, 140, and 400 mg/kg, respectively, with no significant differences attributable to dose. There was an unexplained pattern in maximal concentration and AUC with regard to duration of treatment, with the parameters being highest at week 0, lowest at week 26, and intermediate at week 39. Clearance had the reverse pattern; time of maximal concentration had no pattern.

Administration, Oral↗
PubMed2002

Abrogation of bleomycin-induced lung fibrosis by nitric oxide synthase inhibitor, aminoguanidine in mice.

The effects of aminoguanidine (AG), a specific inhibitor of inducible nitric oxide synthase, on the bleomycin (BL)-induced lung fibrosis was evaluated in mice. The animals were placed into five groups: saline (SA)-instilled drinking water (SA+H(2)O), saline-instilled drinking water containing 0.5%AG (SA+0.5%AG), BL-instilled drinking water (BL+H(2)O), BL-instilled drinking water containing 0.2%AG (BL+0.2%AG), and BL-instilled drinking water containing 0.5%AG (BL+0.5%AG). The mice had free access to H(2)O or H(2)O containing AG and lab chow ad lib 2 days prior to intratracheal (IT) instillation of BL (0.07U/mouse/100 microL) or an equivalent volume of sterile isotonic saline. The mice in the SA+0.5%AG group consumed the greatest amount of AG without any ill effects than the mice in any other group. There were no differences in any of the measured biochemical determinants between the SA+H(2)O and SA+0.5%AG control groups. The IT instillation of BL in the BL+H(2)O group caused significant increases in the lipid peroxidation, hydroxyproline content, and prolyl hydroxylase activity of lungs and influx of inflammatory cells in the broncheoalveolar lavage fluid (BALF) as compared to both control groups. The intake of aminoguanidine by mice in the BL+0.5%AG group caused significant reductions in the BL-induced increases in all measured biochemical indices of lung fibrosis without any effects on the influx of inflammatory cells in the BALF. In fact, AG in both BL-treated groups additionally increased the total cell counts in the BALF from mice in the BL+0.2%AG and BL+0.5%AG groups as compared to the BL+H(2)O group. Histopathological evaluation of the lungs revealed that the mice in the BL+0.5%AG group had markedly fewer fibrotic lesions than mice in the BL+H(2)O group. These results demonstrate that aminoguanidine minimizes the BL-induced lung fibrosis at both the biochemical and the morphological level and support our earlier hypothesis that the production of nitric oxide plays a significant role in the pathogenesis lung fibrosis caused by BL.

Animals↗
PubMed2000

Effect of antibody against integrin alpha4 on bleomycin-induced pulmonary fibrosis in mice.

Integrins are a family of transmembrane glycoproteins that can interact with components of the extracellular matrix. The alpha4beta1 and alpha4beta7 integrins are heterodimeric leukocyte cell surface molecules critical to their cell and matrix adhesive interactions. Evidence for a central role for the alpha4 integrins in leukocyte pathophysiology in the lung is well documented. In this study, we tested the hypothesis that neutralizing antibody for integrin alpha4 (PS2) may reduce bleomycin (BL)-induced lung fibrosis in vivo. Male C57BL/6 mice were injected intratracheally with saline (SA) or BL (0.08 U/mouse) followed by intraperitoneal injection of SA, isotype control antibody (1E6), or PS2 (100 microg) three times a week. Twenty-one days after the intratracheal instillation, mice were killed for bronchoalveolar lavage (BAL), biochemical, histopathological, and immunohistological analyses. Treatment with PS2 significantly reduced BL-induced increases in lung lipid peroxidation and hydroxyproline content. Lung histopathology also showed reduced fibrotic lesions in the BL-treated lungs by treatment with PS2. BL-treated mouse lungs also showed induction of cells with the myofibroblast phenotype, as indicated by the increased expression of alpha-smooth muscle actin (alphaSMA), whereas treatment with PS2 minimized the BL-induced alphaSMA expression. Furthermore, treatment with PS2 reduced the BL-induced increase in the BAL total cell number, and attenuated the BL-induced increase in the BAL protein level. It is concluded that integrin alpha4 may play an important role in BL-induced pulmonary fibrosis, and the use of anti-alpha4 antibody offers therapeutic antifibrotic potential in vivo.

Actins↗
PubMed2000

Characterization of [(3)H]ryanodine binding sites in mammalian lung.

The ryanodine-sensitive calcium channels, also called ryanodine receptors, are intracellular Ca(2+)-release channels that have been shown to bind the neutral plant alkaloid ryanodine with nanomolar affinity. The activity of the skeletal muscle (RyR1), cardiac muscle (RyR2), and brain (RyR3) ryanodine receptor isoforms have been shown to be highly regulated by physiological factors including pH, temperature, and ionic strength; endogenous compounds including Ca(2+), Mg(2+), and adenosine triphosphate (ATP); and pharmacological agents including caffeine, ruthenium red, and neomycin. RyR3 is reportedly expressed in diverse tissues including lung; however, specific [(3)H]ryanodine binding sites in mammalian lung tissue have not been characterized. In this study, hamster lung ryanodine binding proteins were shown to specifically bind [(3)H]ryanodine with an affinity similar to that of RyR isoforms found in other tissues and this binding was shown to be sensitive to Ca(2+) concentration, stimulation by caffeine and spermine, and inhibition by Mg(2+), ruthenium red, and neomycin. The solubilized, intact ryanodine binding protein from hamster lung demonstrated approximately the same 30S sedimentation coefficient as RyR1 and RyR2, but a putative ryanodine receptor subunit from hamster lung was not found to cross-react with antibodies specific for the three known isoforms. We conclude that the hamster lung ryanodine binding protein demonstrates sedimentation and binding characteristics that are similar to those of the known RyR isoforms, but may exhibit antigenic dissimilarity from the typical RyR isoforms found in muscle and brain.

Animals↗
PubMed2000

Suppression of bleomycin-induced nitric oxide production in mice by taurine and niacin.

The effects of taurine (T) and niacin (N) on the influx of inflammatory cells and nitric oxide (NO) levels in bronchoalveolar lavage fluid (BALF) and expression of inducible NO synthase (iNOS) mRNA and iNOS protein in lungs were evaluated in the bleomycin (BL)-mouse model of lung fibrosis. Mice were placed into four groups: saline-instilled (SA) with a control diet (CD) (SA + CD); saline-instilled with TN (1% taurine in water + 2.5% (w/w) niacin in diet) (SA + TN); BL-instilled with CD (BL + CD); and BL-instilled with TN treatment (BL + TN). There was no difference in differential cell counts in BALF between the SA + CD and SA + TN control groups. Intratracheal instillation (IT) of BL (0.1 U/mouse) in mice stimulated an early influx of neutrophils followed by an increase in lymphocytes and macrophages in the BL + CD group. Taurine and niacin treatment significantly reduced the numbers of neutrophils, lymphocytes, and macrophages in the BL + TN group and caused significant reductions in BL-induced increases in the lung hydroxyproline content at 14 and 21 days in the BL + TN group. The mice in the SA + CD and SA + TN control groups had low levels of NO in BALF, whereas mice in the BL + CD group as compared to the SA + CD control group had elevated levels of NO from day 3 through day 21. Taurine and niacin treatment caused significant reductions in BL-induced increases in NO levels in BALF from mice in the BL + TN group at 7, 14, and 21 days as compared to the corresponding BL + CD group. The increases in NO levels in BALF from the BL + CD group were associated with elevated levels of iNOS gene expression and protein in the lungs. RT-PCR analysis of total RNA isolated from the lungs indicated that taurine and niacin treatment suppressed the BL-induced increases in iNOS message and iNOS protein. The ability of taurine and niacin to suppress the BL-induced increased production of NO secondary to decreases in iNOS mRNA and protein appears to be one of the mechanisms for their anti-inflammatory and antifibrotic effects.

Animals↗
PubMed2000

Anti-inflammatory effect of pirfenidone in the bleomycin-hamster model of lung inflammation.

We have previously reported the antifibrotic effects of pirfenidone (PD) in the bleomycin (BL)-hamster model of lung fibrosis. Since the development of fibrosis is generally preceded by acute lung inflammation, the present study was conducted to find out if dietary intake of PD (0.5%) has any effects on BL-induced lung inflammation. In this regard, we evaluated the effects of PD on BL-induced increased pulmonary vascular permeability, increased influx of inflammatory cells and increased levels of TGF-beta in the bronchoalveolar lavage fluid (BALF). Hamsters were intratracheally (IT) instilled with saline (SA) or BL (5.5 units/kg/5 ml). The animals were fed the control diet (CD) or the same diet containing 0.5% PD 2 days prior to IT instillation and throughout the study. The bronchoalveolar lavage was carried out at different times after IT instillation. Lavage fluid was used for total and differential cell counts and BALF-supernatant for measurement of total protein and TGF-beta. IT instillation of BL caused significant increases in total cells, neutrophils, macrophages and lymphocytes and in the levels of total protein and TGF-beta in BALF from hamsters in the BL + CD groups as compared to the corresponding SA + CD control groups. In contrast, treatment with pirfenidone in general, suppressed the BL-induced increases in the levels of proteins and TGF-beta and in the influx of neutrophils, macrophages and lymphocytes in BALF at the early time points in BL + PD groups. Based on the data reported in this study, we conclude that the anti-inflammatory effects of pirfenidone as evident by suppressions of BL-induced increased pulmonary vascular permeability and increased influx of inflammatory cells in the lung contribute additionally to its inherent anti-fibrotic effect.

Administration, Oral↗
PubMed2000

Taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kappaB in mice.

The effects of taurine (T) and niacin (N) on bleomycin (BL)-induced increased production of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1alpha, IL-6, and transforming growth factor-beta (TGF-beta) levels in the bronchoalveolar lavage fluid (BALF), and increased collagen content and nuclear factor-kappaB (NF-kappaB) activation in the lungs were investigated in mice. The mice were intratracheally instilled with saline (SA) or BL (0.1 U/mouse/50 microliter) under ketamine and xylazine anesthesia. They had ad libitum access to diet containing 2.5% niacin (w/w) or the same control diet (CD) and water with and without taurine (1%) 3 days before intratracheal instillation and throughout the study. The mice were sacrificed at different times for collecting BALF and lungs, which were appropriately processed for various measurements. Treatment with taurine and niacin attenuated the BL-induced increases in proinflammatory cytokines such as IL-1alpha, TNF-alpha, IL-6, and TGF-beta in BALF and lung hydroxyproline content of the mice in BL + TN groups. Reverse transcription-polymerase chain reaction analysis of total RNA from whole lung was performed to assess the induction of TNF-alpha and IL-1 mRNAs as markers of NF-kappaB activation. The NF-kappaB DNA-binding activity in whole-lung extract was evaluated by electrophoretic mobility shift assay. This revealed a progressive increase in NF-kappaB activation and IkBalpha depletion in lungs from mice in BL + CD groups from day 1 through day 21 compared with the corresponding SA + CD control groups. Treatment with taurine and niacin generally inhibited the BL-induced increases in the nuclear localization of NF-kappaB and preserved IkappaBalpha protein in BL + TN groups. This may be one of the mechanisms for the antifibrotic effect of taurine and niacin.

Animals↗
PubMed1999

Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters.

BACKGROUND: Transforming growth factor beta (TGF-beta) is a key mediator of collagen synthesis in the development of lung fibrosis. It has previously been shown that the administration of TGF-beta antibody and TGF-beta binding proteoglycan, decorin, reduced bleomycin (BL) induced lung fibrosis in animals. The present study was carried out to investigate whether intratracheal instillation of TGF-beta soluble receptor (TR) would minimise the BL induced lung fibrosis in hamsters. METHODS: The effect of a recombinant TR (TGFbetaRII) on the lung collagen accumulation was evaluated in a BL hamster model of pulmonary fibrosis. Animals were divided into four groups and intratracheally injected with saline or BL at 6.5 U/4 ml/kg followed by intratracheal instillation of phosphate buffered saline (PBS) or 4 nmol TR in 0.3 ml twice a week. Twenty days after the first intratracheal instillation the hamsters were killed for bronchoalveolar lavage (BAL) fluid, biochemical, and histopathological analyses. RESULTS: Treatment of hamsters with TR after intratracheal instillation of BL significantly reduced BL induced lung fibrosis as shown by decreases in the lung hydroxyproline level and prolyl hydroxylase activity, although they were still significantly higher than those of the saline control. Histopathological examination showed a considerable decrease in BL induced fibrotic lesions by TR treatment. However, TR did not prevent the BL induced increases in total cells and protein in the BAL fluid. CONCLUSIONS: These results suggest that TR has antifibrotic potential in vivo and may be useful in the treatment of fibrotic diseases where increased TGF-beta is associated with excess collagen accumulation.

Animals↗
PubMed1999

Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level.

Pirfenidone (PD) is known for its antifibrotic effects in the bleomycin (BL) hamster model of lung fibrosis. We evaluated whether pretreatment of hamsters with PD could influence the effects of BL-induced overexpression of platelet-derived growth factor (PDGF)-A and PDGF-B genes and proteins in the same model of lung fibrosis. We demonstrate elevated levels of PDGF-A and PDGF-B mRNAs in bronchoalveolar lavage (BAL) cells from lungs of BL-treated compared with saline control hamsters by RT-PCR analysis. However, these levels were not altered in BAL cells obtained from BL-treated hamsters on diets containing 0.5% PD. Western blot analysis of BAL fluid for PDGF isoforms demonstrated that PD treatment inhibited the synthesis of both PDGF-A and PDGF-B isoforms. PD treatment also decreased the mitogenic activity in the BAL fluid from BL-treated hamster lungs. Taken together, these data provide evidence that the protective effects of PD against BL-induced lung fibrosis may be mediated by a reduction in PDGF isoforms produced by lung macrophages.

3T3 Cells↗
PubMed1999

Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis.

A time course study was carried out to elucidate the mechanisms for antifibrotic effect of pirfenidone (PD). Hamsters were intratracheally (i.t.) instilled with saline (SA) or bleomycin (BL) (7.5 units/kg/5 ml). The animals were fed a diet containing 0.5% PD or the same control diet (CD) without the drug 2 days before and throughout the study. The animals were sacrificed at various times after instillation. The lung hydroxyproline level in BL + CD groups was gradually increased and peaked at 21 days to 181% of the SA + CD control. The BL + PD-treated groups showed a gradual decrease in their lung collagen content, showing a maximum reduction of 40% at day 21. The lung malondialdehyde levels of the BL + CD groups were increased by several-fold of the corresponding SA + CD groups at various times. The lung prolyl hydroxylase (PH) activities in the BL + CD groups were also increased by several-fold of the corresponding SA + CD groups at these time points. The hamsters in the BL + PD showed a gradual decrease in the lung malondialdehyde levels from 10 to 21days compared with their corresponding BL + CD groups. Treatment with PD also reduced the lung PH activities in the BL + PD groups compared with the corresponding BL + CD groups. However, PD failed to manifest any direct inhibitory effect on PH activity in vitro. BL treatment increased the lung procollagen I and III gene expressions in the BL + CD groups by several-fold at varying times compared with the corresponding SA + CD, and treatment with PD in the BL + PD groups significantly down-regulated the BL-induced overexpression of these genes. Studies evaluating the regulation of these genes at the transcriptional level revealed PD significantly reduced the transcription of PC I at 14 days. Our results indicate that the antifibrotic effect of PD was partly due to suppression of the BL-induced inflammatory events and partly due to down-regulation of BL-induced overexpression of lung procollagen I and III genes.

Animals↗
PubMed1999

Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis.

This study was undertaken to investigate whether treatment with the antifibrotic drug pirfenidone (PD) down-regulates the bleomycin (BL)-induced overexpression of transforming growth factor (TGF)-beta gene in the lungs. Hamsters were intratracheally instilled with SA or BL (6.5 U/kg/4 ml) under anesthesia. They were fed a diet containing 0.5% PD or the same control diet (CD) without the drug 2 days before and throughout the study. After the animals were sacrificed, their lungs were appropriately processed. The BL treatment elevated the total influx of inflammatory cells, including macrophages, by severalfold at different days in bronchoalveolar lavage fluid (BALF) from hamsters in BL + CD groups, relative to the corresponding SA + CD control groups. Treatment with PD significantly (P </=.05) suppressed the influx of inflammatory cells and macrophages at day 7 in the BL + PD groups, relative to the corresponding BL + CD groups. In addition, the levels of TGF-beta in BALF from hamsters in BL + CD groups were elevated by 2.6- to 4.5-fold at different days, relative to the corresponding SA + CD groups. Treatment with PD significantly (P </=.05) reduced the TGF-beta protein in BALF from BL + PD groups at 14 and 21 days, when compared with the corresponding BL + CD groups. The intratracheal instillation of BL significantly (P </=.05) elevated the TGF-beta mRNA at 7, 14, and 21 days in BL + CD groups, relative to the corresponding SA + CD groups, and treatment with PD significantly (P </=.05) suppressed the TGF-beta gene expression in BL + PD groups at these times, when compared with the corresponding BL + CD groups. Nuclear runoff studies revealed that PD suppressed the BL-induced increase in TGF-beta gene transcription by 33%. It was concluded that one of the mechanisms for antifibrotic effect of PD is its ability to suppress the BL-induced overexpression of TGF-beta gene at the transcriptional level.

Animals↗
PubMed1999

Effects of pirfenidone on the generation of reactive oxygen species in vitro.

Pirfenidone is a newly developed antifibrotic drug that has been reported to retard the progression of pulmonary fibrosis induced by bleomycin and cyclophosphamide in animal models of lung fibrosis. The present in vitro studies using noncellular and cellular systems evaluated the antioxidant and cytotoxic properties of this drug. The Fenton reaction [Fe(II) + H2O2 --> Fe(III) + *OH + OH-] and the xanthine/xanthine oxidase system were used as sources of hydroxyl (*OH) and superoxide anion (O2*-) radicals, respectively. Electron spin resonance spin trapping was used for free radical detection and measurement. The reaction rate of pirfenidone with *OH was found to be 1.63 x 10(10) M(-1) s(-1), which is comparable to several well-established antioxidants, such as ascorbate, glutathione, cysteine, azide, and lipoic acid. Compared to *OH radicals, the O2*- scavenging was less efficient 42.36 M(-1) s(-1) with pirfenidone. Pirfenidone was also effective in inhibiting zymosan-stimulated chemiluminescence. In a noncellular model of lipid peroxidation, pirfenidone inhibited crystalline silica-induced lipid peroxidation. The inhibition of crystalline silica-induced cytotoxic reactions and lipid peroxidation combined with the efficient antioxidant properties of pirfenidone indicate that this agent may express its antifibrotic effects partly through its ability to scavenge reactive oxygen species.

Animals↗
PubMed1998

Regulation of transforming growth factor-beta1 mRNA expression by taurine and niacin in the bleomycin hamster model of lung fibrosis.

We have reported that taurine (T) and niacin (N) inhibit the expression of procollagen type I and type III genes at the level of gene transcription in the bleomycin (BL) hamster model of lung fibrosis. In the present study, we have investigated the effects of TN in diet on the temporal expression of transforming growth factor-beta1 (TGF-beta1) mRNA and TGF-beta1 protein production in the same model of lung fibrosis to determine whether the decreased transcription of procollagen genes is associated with downregulation of TGF-beta1 mRNA. Our results demonstrate that expression of TGF-beta1 mRNA in lungs is increased in BL-treated hamsters in the BL + control diet (CD) group, compared to saline controls in the saline-instilled (SA) + CD group, by 3.5-, 2.5-, 4-, and 2-fold at 3, 7, 14, and 21 d, respectively, and TN treatment caused significant decreases in TGF-beta1 mRNA expression in BL-treated animals in the BL + TN group from Day 3 through Day 21. In addition, TN treatment also reduced TGF-beta1 protein in bronchoalveolar lavage fluid (BALF) from BL-treated animals in the BL + TN group. These decreases in TGF-beta1 mRNA and TGF-beta1 protein correlated with decreased lung collagen content in hamsters in the BL + TN group as demonstrated in our earlier study. To confirm that the TGF-beta1 activity observed in BALF is reflected at the transcriptional level, total RNA was isolated from lavaged cells. Reverse transcriptase-polymerase chain reaction analysis demonstrated maximal expression of TGF-beta1 mRNA transcripts in BL-treated lavaged cells from animals in the BL + CD group and only low levels were detected in both saline control groups, and in BL + TN-treated lavaged cells. Nuclear runoff analysis indicated that TN-mediated reduction of TGF-beta1 mRNA steady-state levels was a result of decreased gene transcription, suggesting a transcriptional downregulation mechanism. Our results indicate that the combined treatment with TN ameliorates BL-induced lung fibrosis, at least in part, via inhibition of TGF-beta1 mRNA expression.

Animals↗
PubMed1997

Antifibrotic effect of decorin in a bleomycin hamster model of lung fibrosis.

We reported previously that treatment with antibody to transforming growth factor-beta (TGF-beta) caused a marked attenuation of bleomycin (BL)-induced lung fibrosis (LF) in mice. Decorin (DC), a proteoglycan, binds TGF-beta and thereby down-regulates all of its biological activities. In the present study, we evaluated the antifibrotic potential of DC in a three-dose BL-hamster model of lung fibrosis. Hamsters were placed in the following groups: (1) saline (SA) + phosphate-buffered saline (PBS) (SA + PBS); (2) SA + DC; (3) BL + PBS; and (4) BL + DC. Under pentobarbital anesthesia, SA (4 mL/kg) or BL was instilled intratracheally in three consecutive doses (2.5, 2.0, 1.5 units/kg/4 mL) at weekly intervals. DC (1 mg/mL) or PBS was instilled intratracheally in 0.4 mL/hamster on days 3 and 5 following instillation of each dose of SA or BL. In week 4, hamsters received three doses of either DC or PBS every other day. The hamsters were killed at 30 days following the first instillation, and their lungs were appropriately processed. Lung hydroxyproline levels in SA + PBS, SA + DC, BL + PBS, and BL + DC groups were 965, 829, 1854, and 1387 microg/lung, respectively. Prolyl hydroxylase activities were 103, 289, and 193% of SA + PBS control in SA + DC, BL + PBS, and BL + DC groups, respectively. The myeloperoxidase activities in the corresponding groups were 222, 890, and 274% of control (0.525 units/lung). Intratracheal instillation of BL caused significant increases in these biochemical markers, and instillation of DC diminished these increases in the BL + DC group. DC treatment also caused a significant reduction in the infiltration of neutrophils in the bronchoalveolar lavage fluid (BALF) of hamsters in the BL + DC group. However, DC treatment had little effect on BL-induced increases in lung superoxide dismutase activity and lipid peroxidation and leakage of plasma proteins in the BALF of the BL + DC group. Hamsters in the BL + PBS group showed severe multifocal fibrosis and accumulation of mononuclear inflammatory cells and granulocytes. In contrast, hamsters in the BL + DC group showed mild multifocal septal thickening with aggregations of mononuclear inflammatory cells. Hamsters in both control groups (SA + PBS and SA + DC) showed normal lung structure. Frozen lung sections following immunohistochemical staining revealed an intense staining for EDA-fibronectin and collagen type I in the BL + PBS group as compared with all other groups. It was concluded that DC potentially offers a novel pharmacological intervention that may be useful in treating pulmonary fibrosis.

Animals↗
PubMed1997

Pulmonary structural and extracellular matrix alterations in Fischer 344 rats following subchronic phosgene exposure.

Phosgene, an acylating agent, is a very potent inducer of pulmonary edema. Subchronic effects of phosgene in laboratory animals are not well characterized. The purpose of the study was to elucidate potential long-term effects on collagen and elastin metabolism during pulmonary injury/recovery and obtain information about the concentration x time (C x T) behavior of low levels of phosgene. Male Fischer 344 rats (60 days old) were exposed either to clean air or phosgene, 6 hr/day: 0.1 ppm (5 days/week), 0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1 day/week), for 4 or 12 weeks. A group of rats was allowed clean air recovery for 4 weeks after 12 weeks of phosgene exposure. This exposure scenario was designed to provide equal C x T product for all concentrations at one particular time point except for 0.1 ppm (50% C x T). Phosgene exposure for 4 or 12 weeks increased lung to body weight ratio and lung displacement volume in a concentration-dependent manner. The increase in lung displacement volume was significant even at 0.1 ppm phosgene at 4 weeks. Light microscopic level histopathology examination of lung was conducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4 and 12 and 16 weeks (recovery). Small but clearly apparent terminal bronchiolar thickening and inflammation were evident with 0.1 ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminal bronchiolar thickening and inflammation appeared to be more prominent when compared to the 0.1 ppm group and changes in alveolar parenchyma were minimal. At 1.0 ppm, extensive inflammation and thickening of terminal bronchioles as well as alveolar walls were evident. Concentration rather than C x T seems to drive pathology response. Trichrome staining for collagen at the terminal bronchiolar sites indicated a slight increase at 4 weeks and marked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5 ppm was not examined), 1.0 ppm being more intense. Whole-lung prolyl hydroxylase activity and hydroxyproline, taken as an index of collagen synthesis, were increased following 1.0 ppm phosgene exposure at 4 as well as 12 weeks, respectively. Desmosine levels, taken as an index of changes in elastin, were increased in the lung after 4 or 12 weeks in the 1.0 ppm phosgene group. Following 4 weeks of air recovery, lung hydroxyproline was further increased in 0.5 and 1.0 ppm phosgene groups. Lung weight also remained significantly higher than the controls; however, desmosine and lung displacement volume in phosgene-exposed animals were similar to controls. In summary, terminal bronchiolar and lung volume displacement changes occurred at very low phosgene concentrations (0.1 ppm). Phosgene concentration, rather than C x T product appeared to drive toxic responses. The changes induced by phosgene (except of collagen) following 4 weeks were not further amplified at 12 weeks despite continued exposure. Phosgene-induced alterations of matrix were only partially reversible after 4 weeks of clean air exposure.

Animals↗
PubMed1997

gamma-Linolenic acid-containing diet attenuates bleomycin-induced lung fibrosis in hamsters.

Although bleomycin (BLM), an antineoplastic drug, is used in the treatment of a variety of tumors, the mechanism(s) that contribute to its induced lung injury and fibrosis are not fully elucidated. Since alterations in the levels of certain fatty acid metabolites have been associated with BLM-induced lung injury, we tested the effects of dietary gamma-linolenic acid (GLA)-containing evening primrose oil on BLM-induced morphological alterations in the hamster lung, the marked elevation of tissue hydroxyproline (a marker for collagen synthesis), and elevated generation of arachidonic acid metabolites (marker of inflammatory mediators). Our data revealed that after 14 d of dietary GLA-containing oil (i) BLM-induced elevation of lung hydroxyproline was suppressed (P < 0.05), (ii) the marked BLM-induced elevation of lung leukotriene B4 (LTB4) (a marker of polymorphanuclear generation of proinflammatory LTB4) was significantly suppressed (P < 0.05). The decrease in LTB4 was accompanied by marked elevations (P < 0.05) of lung prostaglandin E1 (PGE1) and 15-hydroxyeicosatrienoic acid (15-HETrE), both with known antiinflammatory properties. Taken together, data from these studies suggest that dietary GLA-containing oil contributes to tissue elevation of PGE1 and 15-HETrE, which in vivo may attenuate lung inflammation and fibrosis.

Animals↗
PubMed1997

Studies on antitussive activity of Drymaria cordata Willd. (Caryophyllaceae).

The methanol extract of Drymaria cordata Willd. was investigated for its effect on a cough model induced by sulfur dioxide gas in mice. It exhibited significant antitussive activity when compared with the control in a dose-dependent manner. The antitussive activity of the extract was comparable to that of codeine phosphate, a prototype antitussive agent. The D. cordata extract (100, 200, 400 mg/kg) showed 11.6%, 31.6% and 51.5% inhibition of cough with respect to the control group.

Animals↗