Obliterative central bronchitis due to mineral dust in patients with pneumoconiosis.

OBJECTIVE: We studied at autopsy a distinctive obliterative bronchitis in three persons with pneumoconiosis and hilar node fibrosis. METHODS: Lungs were evaluated macroscopically, microscopically, and with energy-dispersive spectroscopy. RESULTS: Chest roentgenogram demonstrated right middle lobe syndrome in one patient; bronchostenosis was seen at bronchoscopy in another. The stenotic sites were in perihilar bronchi and showed an upper lobe predominance. Fibrosis with silicotic nodules involved the bronchus, peribronchial tissue, and adjacent lymph nodes. Simple coalworkers' pneumoconiosis was observed in two patients; the third had complicated, mixed dust fibrosis. CONCLUSION: Obliterative bronchitis represents an unusual fibrotic response to free crystalline silica. The process may occur simultaneously in the adjacent lymph node and the bronchial wall; however, it need not be associated with complicated pneumoconiosis. Clinically, obliterative bronchitis may masquerade as bronchogenic carcinoma.

Mutant K-ras oncogenes in colon cancers Do not predict Patient's chemotherapy response or survival

One half of human colon cancers bear mutant c-K-ras oncogenes. Mutant K-ras oncogenes are associated with shortened survival in non-small cell lung cancers, and, in cell line models, with resistance to cis-platinum and to ionizing radiation. This study examines whether mutant K-ras alleles in colon cancer alter patients' response to chemotherapy or survival. We studied 37 patients who received chemotherapy with 5-fluorouracil and leucovorin, Exon 1 of the c-K-ras gene was PCR amplified from DNA extracted from paraffin-embedded tumor blocks. The presence of mutant or wild-type c-K-ras alleles was determined by dideoxy sequencing of the PCR-amplified c-K-ras DNA. c-K-ras mutations at codons 12 or 13 were present in 19 and absent in 18 cases. Responses to chemotherapy were equally likely in patients with either wild-type or mutant c-K-ras, occurring in 28% of patients with wild-type ras and 32% of patients with mutant ras (P = 0.8). Survival was also indistinguishable among both groups. Median survival from diagnosis was 35 months for ras wild-type patients and 31 months for ras mutant patients (P = 0.96). Median survival from starting chemotherapy was 14 months for ras wild-type patients and 17 months for ras mutant patients (P = 0.26). Patients with colon cancers bearing either wild-type or mutant c-K-ras alleles are indistinguishable in overall survival and are equally likely to respond to 5-fluorouracil-based chemotherapy.

Transbronchial biopsy in patients with pulmonary eosinophilic granuloma. Comparison with findings on open lung biopsy.

We evaluated the findings on transbronchial biopsy specimens in reference to open lung biopsy specimens from 12 patients with pulmonary eosinophilic granuloma. Features in transbronchial biopsy specimens were further contrasted to those of patients with interstitial fibrosis and nondiagnostic biopsy specimens for localized lesions. Transbronchial biopsy specimens were randomized and graded for histologic features and cellularity. Patients with eosinophilic granuloma had more macrophages (P < .05) but equivalent numbers of eosinophils, neutrophils, and Langerhans' cells compared with those of the other two groups. Only two endoscopic biopsy specimens were histologically diagnostic or highly consistent with eosinophilic granuloma. We conclude that the diagnosis of eosinophilic granuloma is possible on transbronchial biopsy but requires a high index of suspicion. The demonstration of Langerhans' cells by immunohistochemical staining for S100 protein is a useful adjunct. The low diagnostic yield for eosinophilic granuloma on transbronchial biopsy results from inadequate sampling and from the nonspecific appearance of discrete lesions in small tissue samples.

Reactive eosinophilic pulmonary vascular infiltration in patients with spontaneous pneumothorax.

Prominent nonnecrotizing eosinophilic inflammation of muscular pulmonary arteries was seen in resected lung tissue from two patients with spontaneous pneumothorax. Other histologic features included reactive eosinophilic pleuritis (REP) and fibrobullous disease. Eosinophilic vascular infiltration was not contiguous to REP. In neither patient was there a specific and recognized cause of eosinophilic vasculitis. Both patients are without pulmonary symptoms 1 and 4 years after pneumothorax. Eosinophilic vascular infiltration initially suggested the diagnosis of allergic angiitis or pulmonary eosinophilic granuloma. These diagnoses were excluded by clinical and morphologic data. We subsequently reviewed 30 cases of lung tissue resected from patients with pneumothorax and found REP in 18 patients (60%) and mild pulmonary vascular and perivascular eosinophilia in five patients (17%). REP was present in all cases with eosinophilic vascular infiltration. We conclude that this eosinophilic vascular lesion is an unusual reaction in patients with REP and pneumothorax. Occasionally this lesion mimics allergic angiitis or eosinophilic granuloma. The pathogenesis is probably related to vascular transport of eosinophils to the injured pleural surface.

Neoplasms associated with pulmonary eosinophilic granuloma.

We found a high prevalence of pulmonary and extrapulmonary neoplasms in patients with pulmonary eosinophilic granuloma (PEG) who were studied at our institution. Among 21 patients with PEG, 10 (48%) had associated benign (one patient) or malignant (nine patients) tumors. Patients with tumors were older at the time of diagnosis of PEG (48.9 vs 34.5 years). Tumors included three lung carcinomas, one pulmonary carcinoid tumor, two lymphomas, five extrapulmonary carcinomas, and one mediastinal ganglioneuroma. Two malignant neoplasms developed in each of two patients. Six tumors preceded, three followed, and three occurred concomitantly with the diagnosis of PEG. Slides from eight PEG-associated tumors and 18 control neoplasms from patients without PEG were also stained immunohistochemically for S100 protein. Four PEG-associated (50%) and 11 control (61%) tumors contained S100 protein-positive interstitial cells. Our study suggests, but does not prove, that there may be more than a random association between PEG and neoplasms. Cigarette smoking, moreover, is an important risk factor for both PEG and lung carcinomas. Our immunohistochemical findings indicate that S100 protein-positive cells in tumors usually bear little or no relationship to PEG. In patients with an underlying malignant neoplasm, PEG simulates pulmonary metastases clinically and, occasionally, histopathologically.

Desquamative interstitial pneumonia associated with chrysotile asbestos fibres.

The drywall construction trade has in the past been associated with exposure to airborne asbestos fibres. This paper reports a drywall construction worker with 32 years of dust exposure who developed dyspnoea and diminished diffusing capacity, and showed diffuse irregular opacities on chest radiography. He did not respond to treatment with corticosteroids. Open lung biopsy examination showed desquamative interstitial pneumonia. Only a single ferruginous body was seen on frozen section, but tissue examination by electron microscopy showed an extraordinary pulmonary burden of mineral dust with especially high concentrations of chrysotile asbestos fibres. This report emphasises the need to consider asbestos fibre as an agent in the aetiology of desquamative interstitial pneumonia. The coexistent slight interstitial fibrosis present in this case is also considered to have resulted from exposure to mineral dust, particularly ultramicroscopic asbestos fibres.

Respiratory tract pathology in patients with severe burns.

The histologic spectrum, pathogenesis, and clinical correlates of tracheobronchial and pulmonary lesions were studied by autopsy in six children and 27 adult burn victims. The burns covered a mean total body surface area of 57.7 +/- 23%. The mean survival time was 17.6 +/- 14.3 days. Patients over 60 years tended to survive longer than younger adults, but older patients had less extensive burns (P less than .01). Moderate or severe renal failure was an important clinical complication in 19 patients (58%). Diffuse alveolar damage (DAD) was observed in 16 patients, acute bronchopneumonia in seven patients, and necrotizing pneumonia in seven patients. Both DAD and pneumonia coexisted in 11 patients. Children most consistently developed pneumonia, 6 out of 6 versus 4 out of 17 younger adults (P less than .05). Factors which may have contributed to the pathogenesis of DAD included septicemia (12 patients), hypotension (nine patients), necrotizing pneumonia (six patients), and oxygen toxicity (four patients), in addition to the common presence of inhalational injury. The onset of DAD appeared late in eight patients with long survival periods, suggesting causal factors other than inhalational injury. However, survival rate did not differ in patients with or without DAD, and there was no correlation between DAD and the extent of burns. Airway lesions reflected the length of survival and showed the following sequence of changes: (1) mucosal necrosis and denudation, (2) acute inflammation and ulceration, and (3) squamous metaplasia. Endotracheal intubation injury and superinfection were confounding factors beyond the first few days of survival.

Metabolism of 5-hydroxytryptophan in the isolated perfused rat lung.

The metabolism of 5-hydroxytryptophan (5-HTP) and tryptophan (TRP) in a single pass across the pulmonary circulation was studied in the isolated ventilated perfused rat lung and by high pressure liquid chromatography. The metabolism of 5-HTP was dependent on the rate of lung perfusion and the duration of infusion of 5-HTP, and was a saturable process with an apparent Km of 1.8 mM and Vmax of 0.14 mumol/g/3 min. The indoles found in the lung were 5-HTP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA); only 5-HIAA was detected in the lung effluent. The efflux of 5-HTP from the lung had two exponential components with half-lives of 0.15 and 3.65 min. After an infusion of 3H-5-HTP, the radiolabel that accumulated in lung was located mainly in the soluble fraction. An infusion of TRP resulted in the synthesis of 5-HTP, 5-HT and 5-HIAA in the lung, and 5-HTP was detected in the lung effluent. The results suggest that 5-HT can be synthesized in the intact lung from circulating TRP and 5-HTP. Since the rate of lung metabolism is low and no 5-HT is released into the lung effluent, the contribution of the lung to circulating levels of 5-HT is likely to be insignificant. Synthesis of 5-HT in intact lung suggests an intrapulmonary role for 5-HT.

Regional alveolar damage (RAD). A localized counterpart of diffuse alveolar damage.

Diffuse alveolar damage (DAD) is usually considered a generalized lung process. During five years the authors observed 83 patients with generalized DAD in 827 adult autopsies (10.1%) and 10 patients with identical, but localized, lesions. The authors propose the term regional alveolar damage (RAD) to designate localized "DAD." RAD was unilateral in six patients and most frequently involved the upper lobe. All ten patients had chronic systemic diseases and presented with life-threatening illnesses. The probable causes of RAD were multifactorial and included hypotensive shock, septicemia, pneumonia, hyperoxia, and pancreatitis. All patients developed respiratory failure, requiring supplemental oxygen and, in nine patients, mechanical ventilation. Chest roentgenograms revealed alveolar or combined alveolar and interstitial infiltrates that corresponded to the lesions found at autopsy. The reasons for localization of RAD within the lung are unclear, but the presence of proliferative lesions and frequent involvement of the upper lobe suggests that RAD is not simply an early phase of DAD and implicates additional pathogenetic factors.

High cathepsin B activity in alveolar macrophages occurs with elastase-induced emphysema but not with bleomycin-induced pulmonary fibrosis in hamsters.

Cathepsin B activity was quantitated in alveolar macrophages obtained from hamsters 10, 21, and 105 days after the intratracheal instillation of porcine pancreatic elastase, bleomycin, or normal saline. Alveolar macrophages lavaged from animals receiving elastase contained significantly higher enzyme levels at 21 and 105 days (16,200 and 17,000 U/mg protein/hr, respectively) as compared with saline-treated animals (12,300 units). In contrast, cells from animals receiving bleomycin showed a decrease in activity at 21 and 105 days (9700 and 9900 units, respectively). At 10 days enzyme levels did not differ significantly. The results suggest that cathepsin B levels in alveolar macrophages reflect differences in lung destruction and connective tissue repair in vivo. In addition, the finding of high cathepsin B activity in animals with emphysema suggests the possibility that cysteine proteases contribute to progressive lung destruction initiated by the intratracheal instillation of elastase.

Galactosamine-induced alpha 1-antitrypsin deficiency in rats. Alterations in plasma glycoproteins and alpha 1-antitrypsin carbohydrate composition.

Administration of D-galactosamine (GalNH2) is known to produce alterations in plasma glycoprotein levels, including alpha 1-antitrypsin. The authors have studied the effects of GalNH2 on circulating protein bound carbohydrates and on the plasma concentrations of two alpha 1-antiproteases, transferrin, IgG, and albumin in rats. The alpha 1-antiproteases from GalNH2-treated rats were isolated and their molecular weight, isoelectric point, and carbohydrate composition compared with those of control rat alpha 1-antiproteases. Total plasma protein, albumin, and transferrin levels in the GalNH2-treated rats do not differ significantly from those of control rats. Plasma protein-bound carbohydrate is decreased significantly in the experimental animals, compared with controls: sialic acid decreased 60%, neutral sugars decreased 43%, and amino sugars decreased 38%. The concentrations of alpha 1-antitrypsin (AAT) and a higher molecular weight alpha 1-antiprotease designated AP2 are decreased by 79% and 38%, respectively. AAT isolated from the plasma of GalNH2-treated rats contains 2-3 fewer moles of sialic acid, 3 fewer moles of neutral sugar, and 2 fewer moles of amino sugar per mole of antiprotease than AAT isolated from controls. AP2 from GalNH2-treated rats contains 1 fewer mole each of sialic acid, neutral sugar, and amino sugar per mole of antiprotease than AP2 from controls. These alterations are similar to those seen in humans with genetically determined alpha 1-antiprotease deficiency.

Morphometric analysis of the growth of the normal fetal guinea pig lung.

The structural development of the fetal guinea pig lung is described and quantified morphometrically in this report. At 35 days gestation the lung is in the pseudoglandular phase of growth, by 40 days it is in the canalicular phase, and at 50 days the saccular growth phase has begun. At term (67 days), the fetal guinea pig lung appears mature. From the beginning of the canalicular to the end of the saccular phases, the correlation coefficient between lung volume and gestational age is +.98, between internal surface area and gestational age is +.94 and between total number of saccules and gestational age is +.97. Internal surface area (ISA) correlates closely with lung volume (r = +.99) and the correlation coefficient between total number of saccules and lung volume is +.98. At term, lung volume is 4.22 ml. ISA is 0.5 M2, and total number of saccules is 253 million. Parenchymal growth is achieved by increases in both number and size of airspaces in the canalicular phase, primarily by increases in number during the early saccular phase and largely by increases in airspace size near term. The total length of parenchymal elastic tissue increases from 223 M at 45 days gestation to 5,253 M at term. Elastic tissue fibers first appear in the parenchyma of the fetal guinea pig lung during the canalicular phase, when the rate of saccule formation is high. The quantitative increase in elastic tissue correlates closely with the increase in the total number of saccules from day 45 to day 60 of gestation (r = +.99). The rate of elastic tissue growth increases sharply in the late saccular phase, coinciding with the period of greatest saccular expansion. These data suggest an interdependent relationship between saccular growth, i.e., proliferation and expansion, and the development of lung parenchymal elastic tissue.

Morphometry of hypoplastic fetal guinea pig lungs following amniotic fluid leak.

Deficient quantity of amniotic fluid causes fetal guinea pig lung hypoplasia. Oligohydramnios that lasts only 5 days in early gestation is sufficient to reduce fetal lung growth significantly. We quantitated lung structural alterations at 50 days gestation (term is 67 days) of fetal guinea pigs whose amniotic fluid was drained on day 45 gestation. The study period spans the late canalicular-early saccular phases of guinea pig lung growth. Compared to littermate controls (n = 4), experimental fetuses (n = 5) have reduced lung:body weight ratio (2.81 +/- 0.16 versus 3.21 +/- 0.20 X 10(-2), p less than 0.01), indicating lung hypoplasia. Lung volume is significantly decreased in the experimental fetuses (1.17 +/- 0.15 versus 1.34 +/- 0.07 ml, p less than 0.05). The proportion of lung containing parenchyma (i.e. developing alveoli and alveolar ducts) is reduced following oligohydramnios (0.83 +/- 0.04 versus 0.90 +/- 0.02, p less than 0.025). The hypoplastic lungs contain fewer saccules (fetal "alveoli") (46 +/- 20 versus 69 +/- 23 X 10(6), p less than 0.1) and the surface area that would be available for gas exchange is decreased (698 +/- 234 versus 974 +/- 80 cm2, p less than 0.05). Lung volume and volume proportion of parenchyma are reduced in the experimental lung and therefore diminished parenchymal elastic tissue is anticipated. However, the total length of parenchymal elastic tissue in the experimental lungs is decreased to a surprising degree and is little more than half the length in control lungs (504 +/- 222 versus 974 +/- 70 m, p less than 0.0025). Such marked reduction in total length suggests that factors other than smaller lung size have contributed to the decrease of elastic tissue in the experimental group. In fact, elastic tissue length per unit volume is significantly reduced (509 +/- 189 versus 809 +/- 115 m/cm3, p less than 0.025) indicating an absolute decrease in parenchymal elastic tissue in the hypoplastic lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolation and characterization of alpha 1-antitrypsin in PAS-positive hepatic granules from rats with experimental alpha 1-antitrypsin deficiency.

Chronic galactosamine (GalNH2) administration in rats decreases plasma alpha 1-antitrypsin (AAT) levels to 10-50% of control levels and induces the formation of diastase-resistant, PAS-positive granules, which contain AAT in hepatocytes. This report describes the isolation and purification of hepatic granule AAT by three different methods: solubilization with guanidine hydrochloride followed by gel filtration on Bio-gel A5M, extraction with methylamine and 2-chloroethanol, and solubilization with sodium dodecyl sulfate (SDS) followed by preparative SDS-polyacrylamide gel electrophoresis. All three methods yield a single protein which precipitates with anti-rat plasma AAT antibody, and which has an apparent molecular weight of 45,000 daltons, in contrast to the molecular weight of plasma AAT, 50,000 daltons. Unlike plasma AAT, granule AAT contains no sialic acid, galactose, or fucose. Moreover, granule AAT contains a reduced amount of N-acetylglucosamine and an increased amount of mannose, compared with plasma AAT. The carbohydrate content of granule AAT varies with the isolation procedure used. Granule AAT is susceptible to cleavage by endoglucosaminidase H, which indicates the presence of high-mannose type oligosaccharides. Comparison of the molecular weight, carbohydrate composition, isoelectric point, and endoglucosaminidase H sensitivity of granule AAT isolated from rats with GalNH2-induced AAT deficiency with granule AAT from PiZ humans extends the list of similarities between experimental GalNH2-induced AAT deficiency in rats by and genetically determined AAT deficiency in humans.

Asbestos effects on superoxide production. An in vitro study of hamster alveolar macrophages.

Inhaled asbestos induces accumulation of alveolar macrophages (AM) and polymorphonuclear leukocytes (PMN) in lung. Asbestos-enhanced production of superoxide anion (O2-) by AM and/or PMN may be involved in the pathogenesis of asbestos-induced fibrosis, either through direct effects on collagen synthesis or via mediation of tissue injury and repair. In in vivo experiments, bronchoalveolar lavage (BAL) 3 to 8 weeks following intratracheal asbestos injections showed increases in both PMN and AM, with AM representing 78 to 82% of cells recovered. Inhalation models, generally regarded as more analagous to human exposures, have confirmed AM as the predominant component of the cellular response to inhaled asbestos. In this study, the in vitro effects of asbestos fiber on O2- production by AM have been determined in cell populations derived from the Syrian golden hamster. AM for in vitro study were obtained by BAL. O2- production was monitored as superoxide dismutase (SOD) - inhibitable cytochrome c reduction. Significant rises in O2- release by AM were noted in the presence of 0.4 mg/ml crocidolite (2.53 +/- 0.33 nmole cytochrome c reduced/10(6) cells/30 min, 37 degrees C; controls 1.13 +/- 0.18 nmole; P less than 0.02). Chrysotile induced levels of O2- release in AM which were similar to those evoked by crocidolite.

Tight junction alterations of respiratory epithelium following long-term NO2 exposure and recovery.

Acute exposure to NO2 is reported to disrupt tight junctions in lung epithelium. We have studied the effects of chronic NO2 exposure and recovery breathing clean air to tight junctions of distal airway and alveolar epithelium. Syrian Golden hamsters were exposed to NO2 (30 PPM) for 5 or 9 months and a group of those animals for 9 months were allowed to recover breathing clean air for 3 or 9 months. Animals were sacrificed after 5 and 9 months of NO2 exposure and after 3, and 9 mos. recovery breathing clean air. The lungs were carefully removed, inflation fixed with glutaraldehyde and then processed for freeze fracture and transmission electron microscopy of ultra-thin epon sections. Evaluation of tight junctions of bronchioles and alveoli were disrupted in ultrathin sections and freeze fracture replicas during the period of NO2 exposure. Fibril number, length, degree of fragmentation and orientation were different from age matched controls. The bronchiolar tight junctional fibrils were quantitatively reduced in number and fragmented into much smaller fibril lengths. Alveolar tight junctions were qualitatively disrupted in a similar fashion, however, the sites of damage were focal. During recovery tight junctions in bronchioles did not regain normal fibril number, orientation and continuity, based on quantitative assessment, observed in age matched controls. Alveolar tight junctions remained focally altered. This data indicated that chronic NO2 altered morphologic characteristics of epithelial tight junctions of the lung throughout the period of exposure. The repair process during recovery did not restore the normal tight junction ultrastructural organization observed in age controls. This persistent deviation from the normal is likely to alter and compromise airway epithelial barrier function in the lungs of these hamsters.