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Biomedical subjects

J D Fulmer

Publications and source records attributed to J D Fulmer.

At least 19 recordsLinked to original sources
PubMed1989

Lodoxamide tromethamine prevents neutrophil accumulation in reexpansion pulmonary edema.

Reexpansion pulmonary edema (RPE) is an acute, unilateral lung injury initiated by cytotoxic oxygen metabolites and temporally associated with an influx of polymorphonuclear neutrophils (PMNs); these toxic oxygen products appear to result from reoxygenation of chronically collapsed lung. Lodoxamide tromethamine (U-42585E) reduces infarct size after reperfusion of ischemic myocardium. The possible protective effects of lodoxamide in RPE were examined. Right lungs of rabbits were collapsed for 7 days by injection of air into the pleural space. Reexpansion was accomplished by chest tube with negative pressure in spontaneously ventilating rabbits. Twelve pairs of animals received either lodoxamide (20 mg/kg/h intravenously (i.v.) from 30 min before reexpansion until they were killed) or an equivalent volume of sterile saline. After 2 h, animals were killed by i.v. pentobarbital. Right and left lungs of six pairs of animals were lavaged with 25 ml saline each; the remaining six pairs of animals were studied by measurement of lung wet/dry weight ratio. Albumin concentrations in lavage fluid (BAL) of lodoxamide-treated animals were 243 +/- 165 micrograms/ml in right lung and 29 +/- 15 micrograms/ml in left lung (p less than 0.03); albumin concentration in right lung BAL of untreated animals was 1,180 +/- 319 micrograms/ml (p less than 0.02 vs. lodoxamide-treated animals). PMN percentages in right BAL (3.8 +/- 3.1) and left BAL (2.9 +/- 2.2) did not differ in lodoxamide-treated animals (p greater than 0.65); PMN percentage in right BAL of untreated animals was 18.7 +/- 2.9 (p less than 0.001 vs. lodoxamide-treated animals).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1989

Dietary fish oil inhibits bleomycin-induced pulmonary fibrosis in the rat.

Intratracheal bleomycin induces pulmonary fibrosis in experimental animals, but the mechanisms involved are poorly understood. Since altered levels of fatty acid metabolites are associated with bleomycin-induced lung injury, we examined the effects of a change in dietary fat on bleomycin-induced fibrosis. Previously we have shown that an essential fatty acid-deficient diet can reduce the severity of bleomycin-induced pulmonary fibrosis. The present study examined the effect of replacement of usual dietary fat with menhaden oil, rich in eicosapentaenoic acid, on the development of pulmonary fibrosis. Weanling rats were raised on a standard laboratory diet or a diet consisting of a fat-free powder to which was added 25% (w/w) of menhaden oil. After 8 weeks of feeding, the animals received either 1.5 units of bleomycin or an equivalent volume of saline intratracheally. In animals receiving the laboratory diet, bleomycin treatment produced a 44% increase in total lung protein content when compared to saline-treated controls (p less than 0.001) and a 77% increase in total lung hydroxyproline content (p less than 0.01). In contrast, bleomycin-treated animals receiving the menhaden oil diet had only small increases, which did not reach statistical significance, in protein and hydroxyproline content in the lung. Bronchoalveolar lavage cellularity did not differ among the treatment groups, but the percentage of lavage macrophages was slightly diminished in bleomycin-treated animals receiving the laboratory diet. Cellular differentials of lavage fluid did not differ significantly between bleomycin- and saline-treated animals receiving the menhaden oil diet. Bleomycin-induced histologic changes, quantitated by morphometric analysis, were significantly reduced with the menhaden oil diet. We conclude that a diet rich in eicosapentaenoic acid can significantly ameliorate bleomycin-induced pulmonary fibrosis, possibly via alterations in eicosanoid metabolism.

Animals↗
PubMed1988

Modulation of the development of bleomycin-induced fibrosis by deferoxamine.

Bleomycin is an antineoplastic compound which produces a time- and dose-dependent pulmonary fibrosis. The mechanisms which cause this fibrosis are not known. The ability of bleomycin to produce oxygen radicals in the presence of iron and molecular oxygen appears to be related to the fibrosis. Previous studies, which have examined single time points utilizing the ferric ion chelator deferoxamine and iron-deficient diets, suggest that iron plays a central role in bleomycin-induced pulmonary fibrosis. Therefore, the present study was designed to determine the effects of deferoxamine on the development of bleomycin-induced pulmonary fibrosis. Deferoxamine pretreatment and daily injections resulted in a significant reduction in lung collagen content and lung lipid peroxidation 21 days after intratracheal bleomycin compared with bleomycin treatment alone. In addition deferoxamine treatment significantly inhibited lung DNA increases at 4, 7, and 14 days after bleomycin treatment compared with bleomycin treatment alone. These data indicate that deferoxamine treatment reduces the development of bleomycin-induced pulmonary fibrosis in the later phase. The mechanism might be by the prevention of iron-catalyzed, free-radical formation and modulation of some cellular functions.

Animals↗
PubMed1988

Effect of iron deficiency on bleomycin-induced lung fibrosis in the hamster.

Bleomycin produces a dose- and time-dependent interstitial pulmonary fibrosis in humans, and is widely used to produce an animal model for the study of interstitial pulmonary fibrosis. The mechanism(s) for bleomycin-induced pulmonary fibrosis is (are) unknown, but the production of oxygen radicals by a ferrous ion-molecular oxygen pathway might be related to the fibrosis. Therefore, we studied the effect of iron deficiency on the biochemical, inflammatory, and morphologic parameters of bleomycin-induced pulmonary fibrosis in the hamster. Mild iron deficiency was induced in hamsters by bleeding via the retro-orbital sinus and maintenance on an iron-deplete diet. After intratracheal administration of bleomycin (1 U), there was no accumulation of lung collagen in the iron-deficient bleomycin-treated animals. In comparison, iron-replete animals treated with bleomycin exhibited a significant (p less than 0.01) increase in lung collagen. In addition, bleomycin-treated iron-replete animals had increased lung lipid peroxidation (p less than 0.05), whereas bleomycin-treated iron-deficient animals did not (p greater than 0.05). Lung DNA and morphometric estimates of the lesion severity were significantly increased in both iron-replete and iron-deficient bleomycin-treated animals. These data indicate that iron deficiency is associated with a reduction in the severity of bleomycin-induced pulmonary fibrosis, possibly by the prevention of iron-catalyzed oxygen-radical formation and lipid peroxidation.

Animals↗
PubMed1987

Effects of dietary fats on bleomycin-induced pulmonary fibrosis.

Bleomycin treatment has been used for the experimental induction of pulmonary fibrosis, but the mechanisms involved are poorly understood. Since alterations in the levels of certain fatty acid metabolites have been associated with bleomycin-induced lung injury, we examined the effects of different dietary fats on the development of bleomycin-induced pulmonary fibrosis. Weanling rats were raised on standard laboratory feed or a diet consisting of a fat-free powder to which was added either coconut oil or beef tallow (25% w/w). After 8 weeks of feeding, animals received either 1.5 units bleomycin or an equivalent volume of saline intratracheally. Bleomycin treatment resulted in significant increases in total lung hydroxyproline content in the groups fed the standard lab diet (p less than 0.001) and beef tallow diet (p less than 0.001), but not in the group receiving the coconut oil diet. Furthermore, the lung hydroxyproline content in bleomycin-treated animals was less with the beef tallow diet compared with standard lab feed (p less than 0.05). Bleomycin treatment resulted in an increase in thiobarbituric acid-reactive products, an index of lipid peroxidation, in lungs from animals fed the standard lab diet, but not in the other diet groups. The percentage of diseased lung, as determined by morphometric analysis, was increased in bleomycin-treated animals from all diet groups (p less than 0.05). We conclude that alterations in dietary fats can reduce the severity of pulmonary fibrosis resulting from bleomycin treatment. Possible mechanisms for this effect include alterations in eicosanoid metabolism or changes in immune or effector cell function.

Animals↗
PubMed1985

The effect of bleomycin on lung metabolism of prostaglandin E2 in hamster.

Lung is a major site of prostaglandin synthesis and degradation. One site of metabolism has been shown to be the endothelial cell. Metabolism of prostaglandins has been shown to be influenced by both physiological and pathological mechanism. Furthermore, it has been suggested that a relationship might exist between pulmonary disease and the lung's ability to synthesize and/or degrade prostaglandins. Therefore, we evaluated if bleomycin-induced fibrosis, a model of human pulmonary fibrosis, affects the ability of lung to metabolize prostaglandins. Single pass metabolism of prostaglandin E2 was evaluated in an isolated, perfused and ventilated lung of hamsters at 5 and 500 nM concentrations 4,7,14,21 and 28 days after intratracheal bleomycin. The metabolism of prostaglandin E2 was not changed at the 5 nM level, but was significantly decreased at 500 nM level on day 14 and day 28 after intratracheal bleomycin. The results suggest that intratracheal bleomycin causes alterations in prostaglandin metabolism; the mechanism(s) is unknown but may be related to endothelial cell damage and possible changes in alveolar-capillary surface area.

Animals↗
PubMed1985

The effect of endotoxin on bleomycin-induced lung fibrosis in the rat.

Bleomycin is a commonly used antineoplastic agent which produces dose- and time-dependent pneumonitis and fibrosis in humans. The mechanism of bleomycin-induced lung injury is uncertain. However, current data shows that bleomycin can generate reactive oxygen species such as superoxide and hydroxyl radicals. We therefore investigated whether intraperitoneal (i.p.) injection of endotoxin, a protectant for hyperoxia, could modulate the biochemical and morphological estimates of bleomycin-induced lung fibrosis in rats. However, pretreatment with multiple i.p. injections of endotoxin, combined with intratracheal bleomycin instillation, resulted in increased lung collagen content compared to bleomycin treatment alone and controls. Furthermore, morphological estimates of the severity of lung lesions present in the endotoxin-bleomycin treatment group were increased when compared with saline and endotoxin control lung lesions. These data indicate, in the current study design, that endotoxin did not reduce, but instead increased the severity of bleomycin-induced pulmonary fibrosis in rats. The mechanism for this increase in fibrosis may be the result of pre-existing endotoxin-induced cell injury.

Animals↗
PubMed1985

The effect of deferoxamine on bleomycin-induced lung fibrosis in the hamster.

Bleomycin is a commonly used antineoplastic compound that can produce a dose- and time-dependent pneumonitis and fibrosis in humans. The mechanism of bleomycin-induced fibrosis is not known. However, current data suggest that the production of oxygen radicals by way of a ferrous ion-molecular oxygen mechanism might be related to the pulmonary fibrosis. Therefore, we evaluated the possibility that parenterally administered deferoxamine, an iron chelating compound, could modulate the morphologic and biochemical estimates of bleomycin-induced lung fibrosis in hamsters. Deferoxamine pretreatment and daily injection for 21 days after intratracheally administered bleomycin resulted in a 33% reduction in lung collagen accumulation compared with that after bleomycin treatment alone. However, fibrosis was still present in the bleomycin-deferoxamine group; the animals showed a 142 and 150% increase in lung collagen compared with that in saline- and deferoxamine-treated control animals, respectively. Morphologic estimates of the severity of fibrosis in the bleomycin-deferoxamine treatment group were reduced when compared with the bleomycin treatment group alone, but was increased compared with saline- and saline-deferoxamine-treated control animals. These data indicate that deferoxamine treatment reduces the severity of bleomycin-induced pulmonary fibrosis in hamsters. The mechanism might be by the prevention of iron-catalyzed, free-radical formation.

Animals↗
PubMed1979

Collagenase in the lower respiratory tract of patients with idiopathic pulmonary fibrosis.

To test the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated through collagenase present in the lower respiratory tract, we used the fiberoptic bronchoscope to obtain fluid from the lower respiratory tract of 24 patients with IPF, 18 controls and nine patients with sarcoidosis. The fluid was analyzed for a variety of enzymes, including collagenase. Fifteen of 21 patients with IPF showed collagenase activity, whereas normal controls and patients with sarcoidosis showed none (P greater than 0.001, for all comparisons). In two patients with IPF who were re-evaluated after eight to 24 months, the collagenase activity was persistent. Fluid from patients with IPF also contained elevated levels of a non-specific neutral protease (P greater than 0.01 compared with controls), but there was no elastase activity in fluid from patients with IPF or from controls. The collagenase found in lavage fluid in IPF cleaved lung collagen into collagenase-specific TCA and TCB fragments. We conclude that in IPF the collagen of the lung is subjected to sustained lysis, followed by disordered resynthesis, and that the presence of active collagenase in the lower respiratory tract is a specific feature of the alveolitis associated with this disease.

Adult↗
PubMed1979

Localization of the immune response in sarcoidosis.

Pulmonary sarcoidosis is an interstitial disease characterized by granulomas within the lung parenchyma, anergy to a variety of skin tests, and decreased numbers of circulating T-lymphocytes. To evaluate the effector cell populations present at sites of disease in patients with active pulmonary sarcoidosis, inflammatory and immune effector cells were isolated from lung via bronchoalveolar lavage and compared to comparable cell populations from the peripheral blood of the same patients and similar cell populations of normal subjects and patients with idiopathic pulmonary fibrosis. Patients with sarcoidosis had a marked increase in the percentage of T-lymphocytes in the lung despite a significant peripheral blood T-lymphocytopenia. In addition, many of these T-lymphocytes demonstrated surface marker characteristics associated with lymphocyte activation, and they spontaneously secreted leukocyte inhibitory factor. In contrast to patients with sarcoidosis, normal subjects and patients with idiopathic pulmonary fibrosis had similar percentages of T-lymphocytes in lung and blood, and there was no evidence for T-lymphocyte activation. Analysis of lymphocytes in uninvolved marrow from 7 of 8 patients with sarcoidosis revealed proportions of T-lymphocytes similar to those in the marrows of normal subjects and patients with idiopathic pulmonary fibrosis. In comparison, one patient with sarcoidosis had large numbers of T-lymphocytes in bone marrow, but only in areas where there were granulomas in the marrow. These studies suggest that: (1) the alveolitis of pulmonary sarcoidosis is characterized by large numbers of activated T-lymphocytes, and (2) there is an anatomic localization of the immune response in sarcoidosis in that analysis of uninvolved tissues such as peripheral blood may not reflect local immune responses at sites of granuloma formation.

Adult↗
PubMed1979

Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse.

Evidence from divergent sources suggests that some forms of interstitial pulmonary disease are associated with abnormalities of the cellular immune system. To evaluate whether cellular immune processes are necessary determinants for the development of parenchymal alveolitis and fibrosis secondary to bleomycin, we examined the effect of bleomycin on the NIH, outbred white mouse as compared to the homozygous nude, athymic mouse on the NIH outbred background. The nude mouse has virtually no detectable cell-mediated immune function; we therefore hypothesized that if this component of the immune system were necessary for the development of bleomycin-induced interstitial disease, bleomycin would not induce the same pulmonary lesion in the nude mouse as in the white mouse. However, both white and nude mice developed alveolitis and fibrosis after intraperitoneal administration of bleomycin. Comparison of the frequency and severity of these lesions in the 2 groups revealed no significant differences. These findings suggest that the presence of an intact cell-mediated immune system is not an absolute requirement for the development of bleomycin-induced interstitial disease in the mouse. To the extent that this model is an appropriate approximation of human bleomycin-induced pulmonary disease, these results are consistent with the hypothesis that T-lymphocyte mediated processes are not primary determinants of this lesion.

Animals↗
PubMed1979

Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of lung parenchyma characterized by a chronic inflammatory cellular infiltration and varying degrees of interstitial fibrosis. Current data indicate that the severity of fibrosis and the degree of cellularity determine, in part, the prognosis of IPF and the response to therapy. Whereas lung biopsy gives the best assessement of fibrosis and cellularity, physiologic studies are used to stage and monitor the disease process. To determine which physiologic studies correlate best with severity of fibrosis and degree of cellularity, these parameters were graded in lung biopsies of 23 patients with IPF and compared with a variety of physiologic studies. Although vital capacity, total lung capacity, and diffusing capacity are commonly used as objective monitors of the disease process, none of these parameters correlated with either the severity of fibrosis or the degree of cellularity in biopsy specimens. In contrast, almost all parameters of lung distensibility correlated with the morphologic assessment of degree of fibrosis; compliance had the best correlation. Parameters of distensibility, however, correlated poorly with the degree of cellularity. In comparison, gas exchange during exercise correlated with both morphologic parameters; the exercise-induced changes in arterial oxygen pressure per liter of oxygen consumed had a high correlation with the degree of fibrosis (r = 0.89; P less than 0.001) and correlated to a lesser extent with the degree of cellularity (r = 0.56; P = 0.009). In contrast, neither the resting arterial oxygen tension nor the arterial oxygen tension at maximal exercise correlated with the morphologic assessment of degree of fibrosis or the degree of cellularity. These morphologic-physiologic comparisons suggest that (a) lung volumes and diffusing capacity are poor monitors of both the degree of fibrosis and the degree of cellularity; (b) the fibrotic process contributes, at least in part, to parameters of lung distensibility, and both fibrosis and cellularity contribute to gas exchange alterations during exercise; and (c) parameters of lung distensibility and exercise-induced gas exchange alterations may be useful in staging the severity of disease in IPF.

Adult↗
PubMed1979

Nuclear inclusions in alveolar epithelium of patients with fibrotic lung disorders.

Ultrastructural study of pulmonary biopsy specimens from patients with fibrotic lung disease disclosed the presence of nuclear inclusions in 1% or less of cuboidal alveolar epithelial cells in 9 of 19 patients, including 6 of 12 patients with idiopathic pulmonary fibrosis, 2 of 3 patients with collagen-vascular disease, and 1 of 3 patients with sarcoidosis. Nuclear inclusions were not observed by ultrastructural study in 5 control patients. The inclusions consisted of masses or aggregates of tubules which probably were derived from the inner nuclear membranes. These tubules were smooth-walled, showed branchings and bifurcations, were composed of single trilaminar membranes, usually had a clear content, and ranged from 500 to 1000 A in diameter. They resembled nuclear tubules which occur in other cell types under conditions of rapid growth or specific hormonal stimulation. Statistically significant differences between the groups of patients with and without nuclear inclusions in cuboidal alveolar epithelial cells were not found with respect to smoking history, degree of fibrosis in the lung biopsy specimen, or the degree of pulmonary physiologic impairment. However, the average age of the patients having nuclear inclusions was significantly greater than that of patients not having nuclear inclusions. In addition, the frequency of indentations in the nuclei of cuboidal alveolar epithelial cells was greater in patients with nuclear inclusions than in patients without nuclear inclusions. Highly significant correlations were observed between the presence of nuclear inclusions and the presence of a) anchoring fibrils and hemidesmosomes along the basal surfaces of alveolar epithelial cells and b) multilayering of the alveolar epithelium.

Aging↗
PubMed1979

Ultrastructure of pulmonary mast cells in patients with fibrotic lung disorders.

The topographic distribution, population density, and ultrastructural features of metachromatic cells (mast cells and basophilic leukocytes) were studied in lung biopsies from five control patients and 17 patients with fibrotic lung disorders. The great majority of metachromatic cells were mast cells. The average number of metachromatic cells per square millimeter of tissue section was much larger in patients with fibrotic lung disorders (45.8 +/- 6.5) than in control patients (2.6 +/- 1.6). In control patients, mast cells were most frequently seen in subpleural and perivascular connective tissue. In contrast, the vast majority of mast cells in patients with fibrotic lung disorders was present in thickened, fibrous alveolar septa; mast cells also were found within the alveolar epithelial layer and alveolar lumina. The quantitative distribution of different types of mast cell granules differed in the two groups of patients: granules composed of scrolls were more frequent in control patients, and granules of the combined type (containing mixtures of different components within the same granule) were more frequent in patients with fibrotic lung disorders. Mast cells in the latter patients appeared to migrate through defects in the basement membrane into the epithelial layer and alveolar lumina; mast cells in these areas often showed reduced numbers of granules and disorganized granule content. These changes suggest that pulmonary parenchymal mast cells in fibrotic lung disorders undergo a chronic process of partial degranulation which differs from that found in anaphylaxis; this chronic release of mast cell products may contribute to the continuing alveolar injury and the ventilation-perfusion inequalities observed in the fibrotic lung disorders.

Adult↗
PubMed1978

Distribution of HLA antigens in idiopathic pulmonary fibrosis.

Divergent observations suggest that genetic factors contribute to the susceptibility to or clinical course of idiopathic pulmonary fibrosis. To determine whether there is an association between the major histocompatibility (HLA) system and idiopathic pulmonary fibrosis, the distribution of 35 antigens of HLA loci A and B was determined among 33 white patients with idiopathic pulmonary fibrosis and 329 healthy white control subjects. Although certain antigens tended to be more prevalent among patients with idiopathic pulmonary fibrosis compared with control subjects, there were no significant differences in the phenotype frequencies of the HLA-A and HLA-B antigens between these 2 groups. Thus, although subtle associations may exist between the HLA loci and idiopathic pulmonary fibrosis, these results indicate that antigens of the HLA-A and HLA-B loci are not linked with major risk factors in this disease.

Adult↗
PubMed1978

Gallium-67 citrate scanning in the staging of idiopathic pulmonary fibrosis: Correlation and physiologic and morphologic features and bronchoalveolar lavage.

Idiopathic pulmonary fibrosis is a fatal disorder characterized by interstitial fibrosis and parenchymal inflammation. Current concepts of this disease suggest that the inflammation precedes and probably induces the fibrotic state. To evaluate the extent and relative activity of the inflammatory process, we scanned patients with idiopathic pulmonary fibrosis using gallium-67, a radionuclide known to concentrate in regions of inflammation. To quantify the amount of isotope in the lung parenchyma, the 67Ga-index was developed, a parameter derived from estimates of the size of regional pulmonary uptake, the uptake intensity, and its texture. Evaluation of 67Ga scans in 30 patients with idiopathic pulmonary fibrosis and 19 control subjects demonstrated that the 67Ga-index in the group with idiopathic pulmonary fibrosis was significantly higher (P less than 0.001) than that in the control group. When compared with lung biopsy morphologic studies in 22 patients with idiopathic pulmonary fibrosis, the 67Ga-index correlated with the degree of interstitial cellularity (P less than 0.05) and the degree of alveolar cellularity (P less than 0.005). When compared with cellular analysis of bronchoalveolar lavage fluid in 17 patients with idiopathic pulmonary fibrosis, the 67Ga-index correlated with the differential percentage of neutrophils (P less than 0.05), but not lymphocytes, eosinophils, or macrophages. These studies indicate that 67Ga accumulates in the lungs of patients with idiopathic pulmonary fibrosis and is probably associated with the active inflammatory state. The associations of the 67Ga-index with morphologic features and bronchoalveolar lavage analysis suggest that quantitative evaluation of these scans may be useful in staging the activity of idiopathic pulmonary fibrosis and following responses to therapy.

Adult↗