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Biomedical subjects

J D Fulmer

Publications and source records attributed to J D Fulmer.

At least 55 records · Page 3Linked to original sources
PubMed1980

Chronic airflow obstruction in Fabry's disease.

Seven patients with Fabry's disease, an x-linked sphingolipid storage disorder, were evaluated for the presence and extent of airway obstruction. All were found to have significant obstruction to airflow. In addition, evaluation of their airway epithelial cells obtained by bronchoscopy demonstrated that these cells contained inclusion bodies consistent with deposits of ceramide trihexoside, suggesting that part of their functional obstruction to airflow may be secondary to intrinsic airway disease. Although all of the study population had evidence of airflow obstruction, the impairment was much worse in those who smoked, implying that even mild cigarette smoking is particularly hazardous to patients with Fabry's disease.

Adult↗
PubMed1980

Collagen concentration and rates of synthesis in idiopathic pulmonary fibrosis.

To define the biochemical correlates of the apparent morphologic increase in lung interstitial collagen in idiopathic pulmonary fibrosis (IPF), collagen content was quantitated, and the morphologic degree of fibrosis was assessed in 9 patients with IPF and 6 control subjects. There were no significant differences in the collagen content among patients with IPF compared with that of control subjects. In addition, there was no correlation between collagen content and the morphologic assessment of the degree of fibrosis. Analysis of the collagen content from multiple sites made from base to apex of postmortem material from 3 patients with IPF and 2 control subjects demonstrated a wide, but similar, variation in collagen content in both groups; no definite pattern of anatomic distribution was found in either the patients with IPF or the control subjects. Furthermore, the rates of collagen and noncollagen protein synthesis in explants of lung of patients with IPF demonstrated no significant differences compared with those of the control subjects. The results of this study are consistent with the concept that IPF is a disease of an alteration in quality, form, and location of collagen rather than simply a disease of increased interstitial collagen.

Adult↗
PubMed1980

Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease.

Individuals with serum alpha1-antitrypsin levels below 80 mg/dl are clearly at risk for the development of accelerated panacinar emphysema. One possible approach to the therapy of this disorder would be to raise serum levels of this major antiprotease to establish protease-antiprotease homeostasis within the lung parenchyma. Because danazol, an impeded androgen, elevates levels of C1 inhibitor in patients deficient of that serum antiprotease, we hypothesized that this agent might also increase alpha1-antitrypsin levels in patients with alpha1-antitrypsin deficiency. To evaluate this concept, seven patients with severe emphysema associated with alpha1-antitrypsin deficiency (six PiZ and 1 M(Duarte)Z) and one asymptomatic individual (PiSZ) received 600 mg of danazol daily for 30 d. Five of the six PiZ patients responded to danazol therapy with significant increases in serum alpha1-antitrypsin levels (mean increase of 37%; P < 0.03). The two individuals who were heterozygous for the Z protein increased their serum levels by 85% (PiM(Duarte)Z) and 87% (PiSZ), respectively. These increases in serum alpha1-antitrypsin antigen were accompanied by commensurate increases in serum trypsin inhibition. Crossed immunoelectrophoresis showed no alterations of the microheterogeneity of the alpha1-antitrypsin or the presence of protease-antiprotease complexes in serum during danazol therapy. These data demonstrate that serum alpha1-antitrypsin levels can be augmented by danazol therapy in PiZ individuals as well as those heterozygotes with severe deficiency of alpha1-antitrypsin. The clinical relevance of these increases in serum alpha1-antitrypsin remains speculative, but these findings suggest that danazol may provide a means of improving the protease-antiprotease balance in these individuals and thus impede the progression of their lung disease.

Adult↗
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↗
PubMed1978

Bronchoalveolar lavage in interstitial lung disease.

Cellular and immunoglobulin components of bronchoalveolar fluid recovered by bronchoscopic lavage were evaluated in 32 control patients, 10 normal volunteers, and 60 patients with the following interstitial lung diseases: idiopathic pulmonary fibrosis, pulmonary fibrosis associated with collagen-vascular disease, eosinophilic granuloma, sarcoidosis, and hypersensitivity pneumonitis. The percentage of lymphocytes distinguished two general disease categories: those with increased lymphocytes (sarcoidosis and hypersensitivity pneumonitis); and those with normal lymphocytes (idiopathic pulmonary fibrosis, pulmonary fibrosis associated with collagen-vascular disease, and eosinophilic granuloma). Patients in all five disease categories had elevated IgG levels and percentages of neutrophils compared with control patients, with the highest proportion of neutrophils found in idiopathic pulmonary fibrosis. Immunoglobulin levels also helped distinguish among patient groups, in that patients with hypersensitivity pneumonitis had lavage IgG/albumin ratios greater than 1, whereas patients with sarcoidosis had ratios less than 1; and with infrequent exceptions, the finding of IgM in lavage fluid was limited to patients with hypersensitivity pneumonitis.

Alveolitis, Extrinsic Allergic↗
PubMed1978

Anchoring fibrils. A new connective tissue structure in fibrotic lung disease.

Electron microscopic studies of lung were made and compared in 17 patients with lung disease (10 with idiopathic pulmonary fibrosis, 3 with collagen--vascular diseases, 3 with sarcoidosis, and 1 with chronic eosinophilic pneumonia) and in 5 control patients. In control patients, the alveolar epithelial cells were normal, and no hemidesmosomes were present between the plasma membranes and the basal laminae. In comparison, cuboidal alveolar epithelial cells were present in 15 of the patients with fibrotic lung disease; in 9 of these the alveolar epithelial cells were multilayered. In 7 of the latter 9 patients (5 with idiopathic pulmonary fibrosis and 2 with collagen-vascular diseases), the basal laminae of the alveolar epithelial cells were attached to the plasma membranes by hemidesmosomes and to the underlying interstitial connective tissue by "anchoring fibrils." These fibrils measured from 4000 to 6000 A in length and from 200 to 600 A in width. One or both ends of the anchoring fibrils inserted into thebasal lamina, often forming arcs through which collagen fibrils and connective tissue microfibrils penetrated. Anchoring fibrils showed a complex pattern of transverse banding, which differed from that of collagen and appeared to be symmetric about the center of the fibril. These anchoring fibrils, which resemble those in normal skin and other tissues, were not found in lungs of control patients. In addition, there was a significant correlation between the severity of the pulmonary fibrosis and the presence of anchoring fibrils. These observations suggest that in severe fibrotic lung disease, anchoring fibrils reinforce the attachment of the basal lamina of multilayered alveolar epithelial cells to interstitial connective tissue.

Adult↗
PubMed1977

Fibrosing mediastinitis causing pulmonary arterial hypertension without pulmonary venous hypertension. Clinical and necropsy observations.

Clinical and morphologic observations are described in two patients with severe pulmonary arterial hypertension without pulmonary venous hypertension from fibrosing mediastinitis. In one patient, both main pulmonary arteries and one major pulmonary vein were severely narrowed by dense fibrous tissue; in the second patient, only the right main pulmonary artery was severely narrowed. Both patients had normal intrapulmonary arteries and normal pulmonary parenchyma. Of nine previously described necropsy patients with pulmonary hypertension due to fibrosing mediastinitis, seven had severe narrowing of multiple large pulmonary veins and in six of them the pulmonary hypertension was entirely due to pulmonary venous obstruction. In one other patient, the pulmonary hypertension was due to obstruction of one main pulmonary artery and several large pulmonary veins. Each of these seven previously described patients had severe changes in the small intrapulmonary arteries. Of the other two previously described patients with pulmonary hypertension from fibrosing mediastinitis, one had severe narrowing of only the main right pulmonary artery, and the other, of both main pulmonary arteries. Thus, although pulmonary arterial hypertension in patients with fibrosing mediastinitis is usually due to obstruction of multiple large pulmonary veins and to severe secondary changes in small intrapulmonary arteries, fibrosing mediastinitis can cause severe pulmonary hypertension by obstructing the right or both main pulmonary arteries.

Adult↗
PubMed1977

Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.

To evaluate cellular and protein components in the lower respiratory tract of patients with idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP), limited broncho-alveolar lavage was done in 58 patients (19 IPF, 7 CHP, and 32 controls). Analysis of the cells and protein in the lavage fluids from patients with IPF revealed an inflammatory and eosinophilic response and a significant elevation of IgG in the lungs. With corticosteroid therapy, inflammation diminished but eosinophils remained. Lavage fluid from patients with CHP also had eosinophils and elevated levels of IgG. However, in contrast to IPF, lavage fluid from CHP patients contained IgM, fewer inflammatory cells, and a strikingly increased number (38-74%) of lymphocytes. Identification of lavage lymphocytes in CHP showed that T lymphocytes were significantly elevated and B lymphocytes were decreased compared to peripheral blood. These studies suggest nthat the lung in IPF and CHP may function as a relatively independent immune organ, and that analysis of cells and proteins in broncho-alveolar lavage fluid may be of diagnostic, therapeutic, and investigative value in evaluating patients with fibrotic lung disease.

Aged↗