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T G Christensen

Publications and source records attributed to T G Christensen.

At least 19 recordsLinked to original sources
PubMed2002

Time course of bleomycin-induced lung fibrosis.

Intratracheal instillation (IT) of bleomycin is a widely used experimental model for lung fibrosis. In this study we describe the time-course of bleomycin-induced lung fibrosis in mice using computer-assisted morphometry. C57Bl/6J mice were treated with a single IT dose of bleomycin or control saline. Animals were killed 3, 6, 14 and 21 days post-IT. Lung injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, hydroxyproline concentration in the lung, routine light microscopic examination resulting in a semiquantitative morphological index (SMI) of lung injury, and quantitative morphological measurements (fibrosis fraction and alveolar wall area fraction) aided by optimas image analysis software. Changes in BAL fluid attributed to bleomycin treatment include increased total cell count (days 14 and 21), and increased percentage of neutrophils (days 3 and 6) followed by a sustained increase in lymphocytes (days 6, 14 and 21). Hydroxyproline levels increased in bleomycin-treated mice on days 14 and 21. Median SMI grades were significantly elevated on days 3, 14 and 21. Computer-assisted morphometry demonstrated a 3-fold increase in fibrosis fraction and a 1.3-fold increase in wall area fraction in bleomycin-treated mice on day 14, with no further increase on day 21. These data also demonstrate that the most suitable time point for assessing lung fibrosis in this model is 14 days after IT instillation of bleomycin, based on the observation that at 14 days the animals developed extensive fibrosis, but had less variability in the fibrotic response and lower mortality than later at 21 days. Computer-assisted morphometry provides objective and quantitative measurements that are a useful tool for the evaluation of bleomycin-induced lung injury.

Animals↗
PubMed2001

Human recombinant interferon-alpha2a and interferon-alphaA/D have different effects on bleomycin-induced lung injury.

BACKGROUND: Bleomycin (Bleo)-induced lung injury in mice serves as an animal model of pulmonary fibrosis. The pathogenesis of pulmonary fibrosis remains unclear, but it comprises both inflammatory and fibrotic components. The cytokine interferon (IFN)-alpha is produced by macrophages and may modulate both fibrogenesis and the determination of T lymphocyte phenotype in pulmonary fibrosis. OBJECTIVE: To investigate the effect of two preparations of recombinant IFN-alpha (IFN-alphaA/D and IFN-alpha2a) on Bleo-induced lung injury in C57BL/6 mice. METHODS: Mice were treated by a single intratracheal (IT) instillation of 0.06 mg of Bleo in 0.1 ml of saline or saline alone. One of two different IFN-alpha preparations, IFN-alphaA/D or IFN-alpha2a in saline, or saline alone were administered by daily intraperitoneal injections starting 1 day prior to IT instillation. The treatment groups were as follows: IT Bleo and intraperitoneal saline; IT Bleo and intraperitoneal IFN-alpha2a; IT Bleo and intraperitoneal IFN-alphaA/D; IT saline and intraperitoneal IFN-alphaA/D or IFN-alpha2a; IT saline and intraperitoneal saline. The animals were sacrificed 14 days after IT instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage (BAL) fluid, by a semiquantitative morphological index of lung injury and a quantitative image analysis of cellularity and fibrosis fraction and by biochemical analysis of lung hydroxyproline content. RESULTS: In Bleo-treated mice, IFN-alpha2a treatment caused a significant rise in BAL lymphocytes and in cellularity and fibrosis fractions in lung tissue. In contrast, IFN-alphaA/D treatment had no effect on Bleo-induced lung injury. CONCLUSION: IFN-alpha may enhance Bleo-induced lung injury but this effect varies with different IFN preparations.

Animals↗
PubMed2001

TGF-beta1 induces an accumulation of connexin43 in a lysosomal compartment in endothelial cells.

We have been studying the relationships between cell growth and the expression of the gap junction protein Connexin43 (Cx43) in cultured bovine aortic endothelial cells (BAEC). As part of these studies, we examined the effect of the growth inhibitory cytokine TGF-beta1 on Cx43 expression. We have shown recently that TGF-beta treatment increases Cx43 mRNA and synthesis, content, and half-life of the protein within 24 h, which leads, over the course of days, to an accumulation of Cx43 in large, intensely immunostaining vesicles, filling much of the perinuclear cytoplasmic space. In the current study, based on their distribution and markers, we identified these vesicles as lysosomes/autophagosomes. Cx43 immunostaining and staining with a fluorescent probe for acidic compartments are coincident, as retention of a fluorescent-labeled low-density lipoprotein occurs in a similar pattern and the same staining pattern can be detected in the treated cells using other markers for lysosomal compartments. TEM revealed prominent lysosomal figures with considerable heterogeneous material. After withdrawal of TGF-beta, the accumulated Cx43 was cleared only slowly, with some brightly immunoreactive cells remaining even after 72 h. The prolonged appearance (based on immunoreactivity in situ and in immunoblots) of intact vesicular Cx43 in the treated cells suggests decreased degradation, resulting from impaired lysosomal activity. These data not only emphasize the importance of the lysosome in connexin degradation, but also show that TGF-beta can cause an alteration in lysosomal functioning, with implications for cellular metabolism.

Animals↗
PubMed2000

Hepatic alpha 2 mu-globulin localizes to the cytosol of rat proximal tubule cells.

BACKGROUND: Alpha 2 mu-Globulin (A2), an 18.6 kD protein of hepatic origin, accumulates in the proximal tubule as an abundant, 15.5 kD cleavage product termed "A2-fragment" (A2-f). A2-f facilitates proximal tubule fatty acid oxidation, presumably by binding hydrophobic ligands. This requires some A2-f to enter the cytosol of the renal epithelial cell (REC). The localization of A2/A2-f in the proximal tubule cell was evaluated in this study. METHODS: Immunoblot analysis of renal cortical homogenates separated by differential centrifugation and quantitative immunoelectron microscopy (IEM) was performed to localize A2/A2-f using an affinity-purified antibody that detects both proteins. To evaluate A2 as a physiologically relevant ligand, the accumulation of A2-f in the female rat kidney (normally devoid of A2-f) was examined after the induction of hepatic A2 synthesis. Ligand binding, uptake, and degradation assays were used to assess A2 processing by RECs in vitro. RESULTS: Although A2 and A2-f were detected in the "lysosomal" fraction, only A2-f was found in the soluble protein fraction. IEM confirmed the presence of significant signal in the vesicular and lysosomal as well as the cytosolic compartments. In contrast, both beta 2 mu globulin (B2) and cathepsin B were restricted to endosomes. In the female rat, induction of hepatic A2 production resulted in A2-f accumulation in the renal cortex. In RECs in culture, uptake of A2 and B2 demonstrated nonsaturable, nondisplacable surface binding and similar uptake rates. Compared with B2, A2 was markedly resistant to degradation. CONCLUSIONS: A fraction of A2 escapes lysosomal degradation, permitting A2-f to accumulate in the cytosol of the proximal tubule epithelial cell. A2 may represent an unusual example of a physiologic protein capable of accumulating in a distant cell type.

Alpha-Globulins↗
PubMed1999

Prior heat stress inhibits apoptosis in adenosine triphosphate-depleted renal tubular cells.

BACKGROUND: This study tested the following hypotheses: (a) renal tubular epithelial cells subjected to transient adenosine triphosphate (ATP) depletion undergo apoptosis, and (b) induction of heat stress proteins (HSPs) inhibits cell death following ATP depletion, possibly by interacting with anti-apoptotic signal proteins. METHODS: To simulate ischemia in vivo, cells derived from opossum kidney proximal tubule (OK) were subjected to ATP depletion (5 mM cyanide, 5 mM 2-deoxy-D-glucose, and 0 mM glucose) for 1 to 1. 5 hours, followed by recovery (10 mM glucose without cyanide). The presence of apoptosis was assessed by morphological and biochemical criteria. The effect of prior heat stress or caspase inhibition on apoptosis and cell survival were assessed. RESULTS: In the ATP-depleted cell, both Hoechst dye and electron microscopy revealed morphological features that are typical of apoptosis. On an agarose gel, a "ladder pattern" typical of endonucleosomal DNA degradation was observed. Prior heat stress reduced the number of apoptotic-appearing cells, significantly decreased DNA fragmentation, and improved cell survival compared with controls (73.0 +/- 1% vs. 53.0 +/- 1.5%; P < 0.05). Two different caspase inhibitors also improved survival, suggesting that apoptosis is a cause of cell death in this model. Compared with ATP-depleted controls, prior heat stress inhibited the pro-apoptotic changes in the ratio of Bcl2 to BAX, proteins known to regulate the apoptotic set point in renal cells. HSP 72, a known cytoprotectant, co-immunoprecipitated with Bcl2, an anti-apoptotic protein. Prior heat stress markedly increased the interaction between HSP 72 and Bcl2. CONCLUSIONS: Transient ATP depletion causes apoptosis in tubular epithelial cells. Prior HS inhibits apoptosis and improves survival in these cells. Novel interactions between HSP 72 and Bcl2 may be responsible, at least in part, for the protection afforded by prior heat stress against ATP depletion injury.

Adenosine Triphosphate↗
PubMed1999

The effect of enoxaparin on bleomycin-induced lung injury in mice.

We have evaluated the effect of enoxaparin, a potent antithrombotic drug, on bleomycin (Bleo)-induced pulmonary inflammation in mice. Pulmonary injury was induced by a single intratracheal (i.t.) instillation of Bleo. Four groups of female C57BL/6 mice, each received one of four treatments: (1) i.t. Bleo and daily intraperitoneal (i.p.) injections of enoxaparin (EN) starting one day before i.t. instillation of Bleo (Bleo-EN); (2) i.t. Bleo and i.p. injections of saline (Bleo-Sal); (3) i.t. saline and i.p. enoxaparin (Sal-EN); (4) i.t. saline and i.p. saline (Sal-Sal). Animals were sacrificed 14 days after i.t. treatment. Lung injury was evaluated by analysis of bronchoalveolar lavage fluid and histologically by an overall semiquantitative index of lung injury and a quantitative image analysis assessing alveolar wall area fraction and fibrosis fraction. Treatment of mice with enoxaparin did not ameliorate Bleo-induced lung injury. Our study does not establish a critical role of procoagulant activity in the evolution of Bleo-induced lung injury and does not support the use of antithrombotic therapy for the prevention of pulmonary fibrosis.

Animals↗
PubMed1999

Effect of immunomodulators on bleomycin-induced lung injury.

BACKGROUND: The role of lymphocytes and their subpopulations in lung fibrosis is as yet unclear. OBJECTIVE: To define the role of immunomodulation in bleomycin-induced inflammatory fibrotic lung injury, by testing the effect of two known Th1 inhibitors: linomide and pentoxifylline. METHODS: C57BL/6 mice were treated by a single intratracheal instillation of 0.06 mg bleomycin in 0.01 ml saline or saline alone. Treatment groups included: (1) intratracheal bleomycin and daily treatment with linomide or pentoxifylline; (2) intratracheal bleomycin and daily water; (3) intratracheal saline and daily linomide or pentoxifylline; (4) intratracheal saline and daily water. Linomide and pentoxifylline were available per os in the drinking water from 1 day prior to intratracheal instillation. Animals were studied 14 days after intratracheal instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semiquantitative morphological index of lung injury and a quantitative image analysis of cellularity, fibrosis fraction and alveolar wall area fraction, and by biochemical analysis of lung hydroxyproline content. RESULTS: Linomide or pentoxifylline did not cause any lung injury in saline-treated control mice. Overt signs of lung injury were apparent in bleomycin-treated mice. These changes were not affected by daily treatment with linomide or pentoxifylline, which were given in the highest tolerable dose. CONCLUSION: This study does not support the use of linomide or pentoxifylline to prevent or ameliorate lung fibrosis and may suggest that drug-induced differentiation of T lymphocytes into Th1/th2 subpopulations does not affect the evolution of bleomycin-induced lung injury.

Adjuvants, Immunologic↗
PubMed1997

Phenotypic variation in hamster bronchial mucous cells induced by different airway irritants.

Chronic mucus hypersecretion (CMH), a common feature of various obstructive pulmonary diseases, is caused by a variety of airway irritants. Bronchial mucous cell metaplasia (MCM), a histological correlate of CMH, can be induced in hamster airways by a number of different irritants. Previous studies with the hamster model suggest that the secretory cell response to different agents is not stereotyped but can vary in the type of mucus glycoconjugate produced. The present ultrastructural study was conducted therefore to provide quantitative evidence of phenotypic variation in mucous cells induced independently by exposure to the metaplastic agents elastase and acid. HPA-gold lectin cytochemistry revealed an increase in N-acetyl galactosamine at the cell surface and secretory granules of mucous cells in elastase-treated vs. acid-treated animals. Although there was no quantitative difference between the acid-treated and untreated groups, a difference in the pattern of binding within granules indicated variation in the secretory product. Because mucus glycoconjugates serve as attachment sites for specific pathogens, phenotypically distinct mucous cells may promote differential microbial colonization. In humans therefore, variation in the severity and progression of CMH may be due in part to secretory cell susceptibility and response to different pathogenic stimuli.

Acetylgalactosamine↗
PubMed1996

Immunocytochemical evidence for extra-cellular initiation of elastase-induced bronchial secretory cell metaplasia in hamsters.

The bronchus is the only region of the hamster conducting airways to develop secretory cell metaplasia after an intratracheal instillation of human neutrophil elastase (HNE). We tested the hypothesis that this pathological change occurs because of cellular uptake of the enzyme that is specific to this region. HNE, dissolved in saline, was instilled into the trachea of hamsters, that were sacrificed 5, 15, 30 or 60 min later for immunocytochemical localization of the enzyme. Saline-treated animals served as controls. By light microscopy, HNE was evident only in the lumen and upon the epithelial surface in all airways, at all time points. Saline control tissues were negative. Electron microscopic immunogold staining revealed HNE within luminal macrophages and associated with mucus and, to a limited extent, upon the apical cell surface both in trachea and bronchus. A small amount of HNE staining occurred in the intercellular space and lamina propria of bronchi. Cytoplasmic gold particles were sparse both in treated and control animals. We conclude that instilled neutrophil elastase is excluded from the epithelial cytoplasm regardless of region. We thus reject the hypothesis of airway cellular uptake of HNE and suggest that stimulation of bronchial secretory cells to accumulate mucin granules is initiated at the cell surface, possibly by unmasking or altering region-specific receptors involved in signal transduction pathways governing mucin granule synthesis.

Animals↗
PubMed1993

Oxidants from neutrophil myeloperoxidase do not enhance elastase-induced emphysema in the hamster.

Alpha-1-protease inhibitor is susceptible to oxidative impairment by the neutrophil myeloperoxidase (MPO) system. The purpose of this study was to assess the effect of the MPO oxidant system on elastase-induced emphysema in the hamster. Intratracheal instillation of 200 micrograms of human neutrophil elastase (HNE) induced a significant secretory cell metaplasia (SCM) and airspace enlargement [23% increase in mean linear intercept (MLI) as compared with control values]. Instillation of MPO system components [0.6 international units (U) of MPO, 5.5 U of glucose oxidase and glucose (0.02 M)] along with 200 micrograms HNE failed to enhance the severity of the SCM or emphysema induced by HNE alone. A second experiment was carried out using 50 micrograms of porcine pancreatic elastase (PPE) to induce emphysema. PPE produced a significant 45% increase in MLI, but the MPO system combined with PPE failed to enhance the emphysema induced by PPE alone. The MPO system alone had no measurable effect on airspace size or SCM. In vitro studies showed that PPE was partially inactivated by the MPO system; a 56% loss of elastolytic activity occurred during a 6-min incubation of PPE with the MPO system. This may explain why the MPO system did not exacerbate PPE-induced injury, but it does not explain the lack of enhancement for HNE. A 6-minute incubation of HNE with the MPO system resulted in a nonsignificant 10% decrease of elastolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Relationship of secretory granule content and proliferative intensity in the secretory compartment of the hamster bronchial epithelium.

We have previously shown that normal hamster airway epithelial secretory cells have a lower proliferative intensity than basal cells, but because of their high frequency are a major contributor to cell renewal (Am. J. Respir. Cell Mol. Biol. 1990; 2:51-58). In the present experiment, the relation between proliferative intensity and secretory granule content in bronchial epithelial cells is studied. [3H]thymidine (2 microCi/g wt) was given intraperitoneally, 1 h before killing, to 5 hamsters treated 21 days earlier with intratracheal saline and to six hamsters in which secretory cell metaplasia had been induced by intratracheal treatment with 300 micrograms of human neutrophil elastase given 21 days earlier. Light microscopic autoradiograms were prepared from 2-microns-thick Epon sections of left intrapulmonary hilar bronchi. Cells were categorized as basal, ciliated, secretory, or indeterminate. Secretory cells were classified as either: S1, with 0 to 4 granules; S2, with > or = 5 granules with intervening cytoplasm; or S3, with abundant granules and no apparent supranuclear cytoplasm. Proliferative intensity was defined by the categorical labeling index (LIc) at 1 h after [3H]thymidine injection. LIc was determined by the number of labeled cells in a category as the percent of labeled and unlabeled cells of that category. LIc of each of the cell categories were similar in the elastase and saline groups. LIc was highest for basal cells, reflecting their proliferative intensity, and lowest for ciliated cells. In the saline group, LIc of S1 (0.25%) was significantly higher compared with S2 (0.13%); S3 cells were rare (0.2%) and none were labeled.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Quantitative ultrastructural analysis of the relationship between cell growth, shape change, and mucosecretory differentiation in cultured hamster tracheal epithelial cells exposed to retinoic acid.

Hamster tracheal epithelial cells in extended (32 degrees C) primary culture with and without supplemental retinoic acid (RA) were studied during the proliferative (5 days) and differentiation phases (11 days) by correlative transmission electron microscopy (EM) and light microscopic (LM) autoradiography to quantify the relationship between cell proliferation, shape change, and mucin granule expression. In retinyl acetate-containing control medium, cell numerical density was higher and [3H]thymidine labeling index (LI) lower at day 11 compared with day 5. The addition of 10(-7) M RA to the medium caused an increase in cell numerical density at both times. LI was increased by RA at 5 days and decreased at 11 days. Measurements of cell shape in ultrathin sections adjacent to LM autoradiographs made in the vertical plane demonstrated an RA-induced change from flat to cuboidal at 5 days and a more columnar phenotype at 11 days. Cells containing mucin granules were of two main types based on their ultrastructure. One type, seen at 5 and 11 days, contained diminutive mucin granules and had an LI of 50% at 11 days. Its LI and frequency (26%) were unaltered by RA. The other type, less frequent (15%) and present only at 11 days, was more columnar and contained mucous granules similar to those found in vivo. RA doubled the frequency of this cell type but did not affect its LI (11%). Cells of this type with more than five mucin granules in EM profile did not incorporate thymidine. The data indicate that RA accelerates and enhances cell shape change toward a more cuboidal phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Flurbiprofen does not affect elastase-induced bronchial secretory cell metaplasia in hamsters.

The anti-inflammatory drug flurbiprofen speeds the repair of cigarette smoke-induced bronchial secretory cell metaplasia (SCM) in rats. We tested whether flurbiprofen would prevent or mitigate the development of elastase-induced bronchial SCM in hamsters. Twice daily injections of flurbiprofen (4 or 6 mg.kg-1.day-1) were begun immediately after intertracheal instillation of porcine pancreatic elastase (PPE) or its vehicle, saline. At 3 wks, the bronchi of these animals were compared to those of animals receiving PPE or saline. PPE-treated hamsters, with or without flurbiprofen, developed moderate to severe SCM. Control hamsters had normal airways. Flurbiprofen had no effect on the neutrophilic pulmonary infiltrate seen 2 h after PPE instillation. We conclude that the development of elastase-induced SCM in hamsters is not affected by a flurbiprofen regimen begun directly after elastase instillation. The pathogenesis of this lesion may involve factors which are insensitive to flurbiprofen or which trigger the lesion immediately upon exposure to the enzyme.

Animals↗
PubMed1990

Cell kinetics of normal adult hamster bronchial epithelium in the steady state.

To establish the progenitor role of bronchial epithelial cells in the steady state, we undertook a quantitative autoradiographic study in normal hamsters. Groups of 7 hamsters were killed 1 h and 1, 2, 3, 4, 7, and 14 d after an intraperitoneal injection of [3H]thymidine (2 microCi/g body wt). Autoradiograms were prepared from 861 Epon sections, 2 microns thick, of left intrapulmonary hilar bronchi. Epithelial cells were classified into 1 of 7 categories: basal-1 (B1) and basal-2 (B2), depending on nuclear height; secretory cells denoted as S1 with zero to 4 granules, S2 with 5 or more granules with intervening cytoplasm, and S3 with abundant granules completely filling the cytoplasm; ciliated (C); and indeterminate (IN). Mean silver grain counts decreased significantly over time only for B1 cells (P less than 0.05), with a cell cycle time of 20.6 d and a DNA synthetic time of 7.5 h. Labeled cells, 1 h after thymidine injection, comprised 30.5% S1, 27.8% B1, 22.8% B2, 6.8% IN, 6.4% S2, 5.7% C, and 0% S3 cells. Labeling indices of individual cell categories (LIc), at 1 h after labeling, were highest for B1 followed by B2 cells, reflecting their proliferative intensity. Labeling index of all epithelial cells combined did not change with time, indicating that there was no major cell death or label dilution. The LIc decreased significantly over time only for B1 and B2 cells (P less than 0.001 and P less than 0.002, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Lectin cytochemistry reveals differences between hamster trachea and bronchus in the composition of epithelial surface glycoconjugates and in the response of secretory cells to neutrophil elastase.

Hamsters exposed to an intratracheal instillation of human neutrophil elastase (HNE) accumulate an abnormally high number of secretory granules in bronchial but not tracheal epithelial cells. We employed lectin cytochemistry to investigate possible differences in the epithelial cell surface glycoconjugate layer in trachea compared to bronchus which might explain the regional dissimilarity in response to HNE. Portions of glutaraldehyde-fixed trachea and bronchi were incubated in one of several ferritin-labeled lectins prior to embedding for transmission electron microscopy. Lectins from Ricinus communis, Helix pomatia, and Triticum vulgaris bound to the surface of tracheal secretory cells in moderate to profuse amounts, while most bronchial secretory cells showed little or no label with these lectins. Gold-labeled Helix pomatia agglutinin (HPA), a lectin specific for secretory cells, showed a decrease in surface binding to all tracheal secretory cell types within 2 h of HNE instillation, compared to saline controls. In contrast, the majority of bronchial secretory cells showed an HNE-induced increase in surface label from extremely low levels in saline controls. The low levels of lectin binding to bronchial cells, in contrast to the trachea, may indicate the lack of a protective surface glycoconjugate coat, thus explaining the vulnerability of these cells to HNE. The rise in number of accessible HPA binding sites on the surface of bronchial secretory cells exposed to HNE may represent an important event in the pathologic accumulation of secretory granules by these cells.

Animals↗
PubMed1990

Recombinant human secretory leukocyte-protease inhibitor: in vitro properties, and amelioration of human neutrophil elastase-induced emphysema and secretory cell metaplasia in the hamster.

Studies were undertaken to evaluate the in vitro properties of recombinant human secretory leukocyte-protease inhibitor (rSLPI) that had been made in Escherichia coli in an inactive form and refolded, and to determine whether emphysema and bronchial secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be amelio-rated by prior intratracheal instillation of rSLPI. Chromatographic studies indicated that 3H-rSLPI formed a 1:1 complex with HNE. Blockage of the active site of HNE by a covalently bound tetrapeptide chloromethyl ketone reduced complex formation with 3H-rSLPI by more than 98%. Incubation of 3H-rSLPI-HNE complex with alpha 1-protease inhibitor for 3 hours at 37 degrees C decreased the amount of complex compared with incubation in the presence of bovine serum albumin (70% vs 27% dissociated). The calculated dissociation rate constant was 1.1 x 10(-4) sec-1, indicating a 1.8 hour dissociation half-life. Dissociated 3H-rSLPI retained its ability to recombine with HNE. rSLPI was as effective at inhibiting HNE released from stimulated neutrophils as 3H-rSLPI was at inhibiting purified HNE. Intratracheal pretreatment of hamsters with 3000 micrograms of rSLPI as long as 8 hours before the intratracheal instillation of 250 micrograms of HNE, resulted in significant protection against induction of emphysema and secretory cell metaplasia. One and 4 hours after instillation of rSLPI, 59% and 44%, respectively, of the initial functional activity was recovered in lung lavage supernatant, indicating a half-life of approximately 2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters.

A study was undertaken to determine whether emphysema and airway secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be moderated by pretreatment with human alpha 1-protease inhibitor (API). API (4.9 mg) was given intratracheally to hamsters 1 h before 0.3 mg HNE. Eight weeks later, lung volumes and pressure-volume relationships were measured in the anaesthetized animals. Mean linear intercepts and secretory cell indices were measured in lung sections. API given 1 h before HNE moderated the development of bronchial secretory cell metaplasia. The severity of emphysema was reduced by 75%. Clearance studies indicated that 80% of the functional activity of instilled API could be lavaged from the lungs after 1 h, indicating a 4 h half-life in the lavageable compartment of the lungs. We calculate that for 50% protection from emphysema the molar ratio of lavageable API to HNE at the time of HNE instillation was 4.8 as compared with 0.78 for 50% inhibition of elastolytic activity in vitro, indicating that API is only 16% as efficient in vivo as compared with its in vitro HNE inhibitory effectiveness. Nevertheless, we conclude that human API given intratracheally is efficacious against HNE-induced emphysema and secretory cell metaplasia.

Animals↗