Development of Bullous Disease during Treatment of Pulmonary Marginal Zone B-Cell Lymphoma.

We describe an unusual case of severe pulmonary bullous disease developing during treatment of marginal zone B-Cell lymphoma (MALT) involving the pulmonary parenchyma. The patient originally presented with pneumonia-like symptoms along with hemoptysis and was diagnosed with MALT lymphoma after a video-assisted thoracic surgical (VATS) lung biopsy. Computed tomography (CT) of the chest at diagnosis revealed multiple opacities, but no bullous disease. During the ensuing 4 years, and while on chemotherapy for the MALT lymphoma, sequential CT and pulmonary function tests revealed the development of progressive bullous disease resulting in the replacement of large portions of the lung parenchyma with bilateral bullae. This complication is rare, has been reported only once before in a patient with concomitant amyloidosis, and may be related to activation of proteolytic enzymes by lymphoma cells or chemotherapeutic agents.

Plasmacytoma and upper airway obstruction.

Extramedullary plasmacytomas are hematologic malignancies that occur primarily in the head and neck region. They usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses and present as soft tissue masses, but have not been previously reported to cause airway obstruction. In general, detection of plasmacytoma antedates the eventual development of the systemic hematologic malignancy, multiple myeloma, by months or years. We describe a unique case of acute upper respiratory tract obstruction secondary to compression by an extramedullary plasmacytoma occurring in the neck of a patient with history of long-standing multiple myeloma. Upper airway obstruction may be a manifestation of untreated plasmacytoma. It is imperative for otolaryngologists and head and neck surgeons to be familiar with this entity because total excision, as well as radiation therapy, for plasmacytomas can be curative in patients without underlying overt plasma cell dyscrasias.

Role of tumor necrosis factor-alpha in regulating fibrotic lung repair.

To study the role of tumor necrosis factor-alpha (TNF-alpha) in fibrotic lung repair, we evaluated changes in lung TNF-alpha content and binding during the evolution of the fibrotic response. We concomitantly examined the effect of TNF-alpha on lung fibroproliferative responses. Lung TNF-alpha increased early after injury, at a time when lung tissue and lung fibroblasts exhibited increased binding to the cytokine. Fibroblasts isolated during this phase, which have increased spontaneous proliferative activity, had significant reduction in DNA synthesis when exposed to TNF-alpha. In contrast, DNA synthesis in normal and repair phase fibroblasts was inhibited by TNF-alpha. We also examined mechanisms of transduction of the TNF-alpha fibroproliferative signal, and observed that phosphorylating enzymes and G-proteins were involved. We conclude that TNF-alpha has a dual role in fibrotic repair. During injury, when uncontrolled fibroblast proliferation occurs, TNF-alpha production is increased to slow down the fibroproliferative response. During repair, when fibroblasts participate in structural restitution, TNF-alpha plays a salutary role by stimulating cellular proliferation. These effects of TNF-alpha on cellular proliferation are mediated by activation of two separate signal transduction pathways, phosphorylating enzymes and G-proteins. The observed variability in the effect of TNF-alpha may be related to changes in the phenotypic and genotypic characteristics of repairing lung fibroblasts which alter their responsiveness to exogenous stimuli.

G-protein activation and expression in lung injury.

Lung injury and repair are characterized by changes in the phenotypic and functional characteristics of parenchymal cells. It is not known to what extent these changes are regulated by alterations in total G-protein activity or expression of G-protein subfamilies. G-proteins (GTPases) are receptor-associated proteins that act as molecular switches for signal transduction pathways. They are involved in regulating ribosomal protein synthesis, transmembrane signaling of hormones and growth factors, cellular differentiation and proliferation and guiding organelle movement within cells. In this study, we validated, modified and optimized the experimental conditions needed to evaluate GTPase activity in the lung. We also measured changes in GTPase activity and the expression of G-protein subfamilies in lungs undergoing paraquat lung injury. Total GTPase activity as well as the expression of Gi, Gs, and Go subfamilies demonstrated a sharp increase on day 1 after injury, a time previously shown to coincide with rapid cellular proliferation and increased protein synthesis. In contrast to the other subfamilies, expression of the alpha subunit of the Gs subfamily was more intense and sustained during the repair phase (day 14). These findings implicate G-proteins in general, and the Gs subfamily, in particular, in regulating cellular function during lung repair.

Changes in tumor necrosis factor in postpneumonectomy lung growth.

So that changes in production and binding of tumor necrosis factor-alpha during postpneumonectomy lung growth could be determined, rats underwent left lung resection and were killed 3, 7, or 14 days later, 1 hour after the injection of 3H-thymidine. Serum was collected, and the lungs were lavaged and perfused in vitro. Lung volumes were measured. Lungs were homogenized, and changes in lung weight, protein content, deoxyribonucleic acid content, deoxyribonucleic acid synthesis, and tyrosine kinase activity of different lobes were recorded. Tumor necrosis factor-alpha content of serum, lavage fluid, and perfusate was measured by an enzyme-linked immunoassay. The binding of tumor necrosis factor-alpha to membrane extracts of lung homogenates was measured by immunoblots. Whereas the cardiac lobe of the remaining right lung demonstrated larger increases in size than other lobes after pneumonectomy, there was no difference in any growth parameter between it and the other lung lobes. Serum tumor necrosis factor-alpha was detectable in sham-operated animals and increased significantly after pneumonectomy. However, by day 14, it was not different from the level in sham-operated animals. In contrast, tumor necrosis factor-alpha in lavage fluid remained significantly elevated, and its binding increased gradually throughout the study period. Tumor necrosis factor-alpha in perfusate did not demonstrate any rise. We conclude that lung growth after pneumonectomy is uniform among various lobes, which suggests that it is regulated by humoral factors. Because tumor necrosis factor-alpha, a cytokine known to stimulate cellular proliferation and matrix synthesis, is produced and bound to the lung during this process, it may be one of the humoral factors implicated in postpneumonectomy lung growth.

Idiopathic bronchiolitis obliterans with organizing pneumonia. An acute and life-threatening syndrome.

Idiopathic bronchiolitis obliterans with organizing pneumonia (BOOP) is a clinicopathologic syndrome characterized by an indolent course and favorable prognosis. This report describes five patients with a fulminating and life-threatening variant of this syndrome. Four patients presented with respiratory failure requiring respiratory assistance and positive pressure ventilation. Early recognition of the entity and prompt initiation of corticosteroid therapy in three patients was instrumental in preventing mortality. Our findings suggest that idiopathic BOOP may be the underlying pathology in a number of patients presenting with ARDS. Since corticosteroid therapy may improve survival in these patients, clinicians should heighten their index of suspicion for this entity. Early histologic diagnosis and initiation of corticosteroid therapy should be considered in patients with unexplained ARDS.

Dynamic changes in the functional characteristics of the interstitial fibroblast during lung repair.

To evaluate the mechanisms involved in the regulation of fibroblast function during the repair of fibrotic lung injury, we isolated lung fibroblasts from adult male Fischer-344 rats before the induction of severe unilateral paraquat lung injury, as well as 1 and 14 days later. Fibroblasts were utilized at an early generation time to avoid senescence. In general, fibroblasts of injured lungs displayed significant increases in proliferative and matrix synthesis properties, with more pronounced increases detected early after the induction of injury. This was true of DNA synthesis, which increased by 3- and 1.4-fold on days 1 and 14, respectively; tyrosine kinase activity, which increased by 4- and 3.5-fold; fibronectin synthesis, 14- and 8-fold, respectively; and glycosaminoglycans synthesis, 4.4- and 3-fold, respectively. The increase in function of fibroblasts isolated from the immediate influence of extrinsic growth factors suggests that fibroblast function during repair may be under intrinsic as well as extrinsic control. In the early phases of repair, intrinsic changes may be more dominant and may result in autoregulation of fibroblast function. In the later phases of repair, despite some reduction in intrinsic fibroblast activation, exposure to extrinsic growth factors may result in maintaining the state of activation and in sustaining the repair process.

Changes in tissue fibronectin in elastase induced lung injury.

We studied changes in rat lung fibronectin (FN) content and synthesis after endobronchial administration of elastase. A severe hemorrhagic neutrophilic alveolitis ensued with plasma protein leakage, initial rise in tissue FN content, and sustained rise in FN synthesis. Unlike fibrotic models where initial rises in tissue FN levels are sustained, levels in this model normalized promptly. This, in the setting of increased synthesis is consistent with increased degradation. This degradation of tissue FN may result in the disruption of the lung architecture, interfere with the deposition of newly synthesized matrix and could partly explain the development of emphysema in a model where excess fibronectin synthesis is observed.

Compensatory growth in fibrotic lung injury.

We induced severe left-sided lung fibrosis by the unilateral endobronchial instillation of paraquat (1.0 mg/kg) into the left lungs of adult Fischer 344 male rats. Growth of the contralateral lung as well as its proliferative activity were measured 6 or 14 days later. Whereas the left lung underwent severe fibrosis and shrinkage with more than 85% reduction in lung volume, the right lung more than doubled in size. In addition, there was a significant increase in total protein content, DNA content, and DNA synthesis. We conclude that unilateral lung injury resulting in ipsilateral fibrosis and loss of parenchyma is associated with compensatory growth of the contralateral lung.

Central neurogenic hyperventilation in invasive laryngeal carcinoma.

We describe a patient with central neurogenic hyperventilation secondary to extension of a laryngeal tumor into the base of the brain, resulting in extrinsic compression of the medulla. Such an association has not been previously described. Unique features which distinguish this patient from previously reported cases are emphasized. Possible mechanisms involved in pathogenesis, as well as types of therapy, are outlined.

Steroid responsiveness of fibroblasts of paraquat injured lungs.

We evaluated the effect of dexamethasone on the synthesis of fibronectin by rat lung fibroblasts. A dose dependent inhibition was observed in fibroblasts isolated from normal lungs and in fibroblasts isolated early (4 days) and late (14 days) after the administration of endobronchial paraquat, and was more pronounced in fibroblasts exposed to dexamethasone for longer durations of time. Fibroblasts isolated early were more responsive to the inhibitory effects of dexamethasone on fibronectin synthesis. In addition, the distribution of fibronectin between the cellular and the extracellular compartments in these cells was altered. We conclude that fibroblasts of repairing lungs undergo changes in their responsiveness to corticosteroids during the repair process and are more susceptible to such therapeutic agents during the acute phase of injury.

The role of physician-assistants in critical care units.

We evaluated the feasibility of utilizing physician assistants as providers of primary care in a medical ICU. After a three-month period of rigorous training, two PAs were assigned to the ICU. Their performance as well as the operation of the ICU over a two-year period was evaluated and compared to two preceding years when it was operated by house officers. There were no changes in occupancy, mortality or the rate of complications. Evidence for more careful evaluation of patients prior to admission and discharge, manifesting as slightly fewer admissions and slightly longer duration of hospitalization, was also documented. We conclude that properly trained PAs may have a role in providing health care in intensive care settings.

Effect of transforming growth factor beta on synthesis of glycosaminoglycans by human lung fibroblasts.

The processes of lung growth, injury, and repair are characterized by alterations in fibroblast synthesis and interstitial distribution of extracellular matrix components. Transforming growth factor beta (TGF-beta), which is postulated to play a role in modulating lung repair, alters the distribution of several matrix components such as collagen and fibronectin. We studied the effect of TGF-beta on the synthesis and distribution of the various glycosaminoglycans (GAGs) and whether these effects may explain its role in lung repair. Human diploid lung fibroblasts (IMR-90) were exposed to various concentrations of TGF-beta (0-5 nM) for variable periods of time (0-18 h). Newly synthesized GAGs were labeled with either [3H]glucosamine or [35S]sulfate. Individual GAGs were separated by size exclusion chromatography after serial enzymatic and chemical digestions and quantitated using scintillation counting. There was a dose-dependent increase in total GAG synthesis with maximal levels detected after 6 h of exposure. This increase was noted in all individual GAG types measured and was observed in both the cell associated GAGs (cell-matrix fraction) as well as the GAGs released into the medium (medium fraction). In the cell-matrix fraction, TGF-beta increased the proportion of heparan sulfate that was membrane bound as well as the proportion of dermatan sulfate in the intracellular compartment. In the medium fraction, TGF-beta increased the proportion of hyaluronic acid, chondroitin sulfate and dermatan sulfate released. We conclude that the role of TGF-beta in lung growth and repair may be related to increased synthesis of GAGs by human lung fibroblasts as well as alterations in the distribution of individual GAGs.

Tyrosine kinase activation during lung injury, fibrosis, and compensatory lung growth.

Endobronchial instillation of paraquat into left lungs of rats resulted in ipsilateral fibrosis (evaluated by light and electron microscopy) and compensatory growth of the contralateral lung. Tyrosine kinase (Tyr-K) activity rose early in the fibrotic lung, peaked to a value 4 times the controls on day 3, and remained elevated on day 14. In the right lung, slight increase in activity occurred only on day 5. Cellular proliferative activity was inhibited in both lungs early after injury. In the right lung, however, DNA synthesis increased to levels 10 times the controls by day 7. In the left lung, the inhibition decreased gradually after day 7, indicating increased cellular proliferation. We conclude that activation of some cellular Tyr-K may play a role in regulating early cellular proliferation during lung injury, fibrosis, and compensatory growth.

Post-infectious ARDS: mechanisms of lung injury and repair.

Lung infections are considered the most common causes of ARDS. Additionally, superimposed secondary lung infections may occur in the setting of ARDS and further aggravate lung damage. Substances released by neutrophils are the major mediators of lung injury, although other factors, such as endotoxin, exotoxins, macrophages, and immune mechanisms, are significant contributors. Neutrophil-induced lung injury results from the production of oxygen radicals, the release of products of arachidonate metabolism, and the activation of lysosomal enzymes. The development of ARDS is associated with high mortality. Although a large proportion of survivors eventually recover adequate lung function, some patients progress to severe fibrosis. Experimental evidence suggests that the development of fibrosis results from increased synthesis of ECM components by lung fibroblasts. Fibroblast synthesis of ECM components is normally influenced by alveolar cells, by circulating growth factors, by the external milieu, and by the extent of gene expression of the specific ECM components. These factors undergo significant alterations during the evolution of experimental lung fibrosis. Growth factors are more abundant, alveolar cells are activated, and gene expression is enhanced. These factors, which play a crucial role in promoting experimental lung fibrosis, are likely to be involved in the pathogenesis of fibrosis in post-infectious ARDS.

Effect of subcellular matrix on glycosaminoglycan synthesis by human lung fibroblasts.

The influences modulating glycosaminoglycan production by lung cells are not well understood. We examined the effect of three different subcellular matrices, plastic, type I collagen, and reconstituted basement membrane-like material (RBM), on the synthesis of sulfated glycosaminoglycans by cultured IMR-90 human lung fibroblasts. Accumulation of 35SO4-labeled glycosaminoglycans into the cell-matrix layer or medium was measured. Cells on collagen synthesized significantly less total glycosaminoglycans than cells on plastic but had a higher fraction of labeled glycosaminoglycans present in the cell-matrix layer (35 vs. 18%) with the increases being highest for dermatan and chondroitin sulfates. Cells grown on the RBM synthesized significantly more glycosaminoglycans than cells on plastic or collagen and also had 260% more labeled glycosaminoglycans present in the cell-matrix layer than cells on plastic. We conclude that the matrix to which lung fibroblasts are exposed can influence the amount and type of glycosaminoglycans synthesized and the degree of incorporation into the matrix. This may be relevant to fibrotic lungs with increased type I collagen or to severely injured lungs in which intra-alveolar fibroblasts are in contact with denuded basement membranes.

Changes in lung tissue fibronectin content and synthesis during postnatal lung growth.

We studied changes in lung tissue fibronectin content and synthesis during postnatal lung growth in rats. We reasoned that fibronectin, which is important in cell differentiation, migration, and adhesion, and in the organization of the extracellular matrix, might play a role in the rapid cell proliferation and alveolar septal formation that occurs postnatally in mammalian lungs. Newborn rats were sacrificed at 4, 7, 11, 14, and 21 days after birth. The lungs were perfused and lavaged, tissue fibronectin was extracted using urea and heparin (Bray et al, Science 1981; 214:793) and the extracted fibronectin was measured by enzyme-linked immunoassay. Tissue fibronectin synthesis was measured by the in vivo incorporation of 35S-methionine into fibronectin that was extracted from lung tissue and immunoprecipitated. Lavage fibronectin and albumin content and lung tissue collagen (hydroxyproline) content were also determined. Lung tissue fibronectin content per g dry lung almost doubled between days 4 and 7 after birth, was slightly higher at day 14 than at day 7, and decreased sharply between days 14 and 21. Lung tissue fibronectin synthesis per g dry lung increased steadily between days 4 and 14 to reach a peak value of about 2.5 times the 4-day value; it then decreased sharply between days 14 and 21. The period of increased fibronectin content and synthesis (4 to 14 days) coincided with the period during which lung cell proliferation and secondary alveolar septa formation are known to be the most active, and the sharp decrease in fibronectin content and synthesis (between 14 and 21 days) coincided with the period during which lung growth and remodeling markedly decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Repair of chronic hyperoxic lung injury: changes in lung ultrastructure and matrix.

We studied changes in lung ultrastructure, fibronectin, and collagen during repair of chronic hyperoxic lung injury induced by exposure of rats to 85% oxygen for 14 days. Morphologically, the most persistent changes were in the alveolar interstitium. After 28 days of repair, the extracellular matrix volume was still twofold normal. Total interstitial cell numbers also remained high and interstitial myofibroblast number actually doubled between Days 7 and 14. These changes contrast markedly with repair of acute lung injury induced by 100% oxygen (Thet et al. (1986) Exp. Lung Res. 11, 209-228) in which matrix volume and interstitial myofibroblast number increased initially but then returned to normal. Biochemically, tissue-associated fibronectin was high initially and peaked at 3 days before slowly declining. Tissue collagen content began to increase after the peak in fibronectin content and was over 150% of controls at 28 days; this correlated with an increase in visible collagen fibers. We conclude that changes in lung morphology and matrix after chronic hyperoxic lung injury are more persistent than after acute hyperoxic lung injury and result in a greater degree of chronic interstitial fibrosis.

Unilateral paraquat-induced lung fibrosis: evolution of changes in lung fibronectin and collagen after graded degrees of lung injury.

We describe a model of pulmonary fibrosis in which doses of paraquat ranging from 0.001 mg/kg to 1.0 mg/kg were instilled into the right lung of rats. Lung injury, as measured by right lung lavage albumin content and differential neutrophil count, ranged from undetectable to extremely severe, depending on the dose. Lung fibrosis, as assessed by collagen content and electron microscopy, showed similar dose-response effects. Mortality was minimal. Lavage fibronectin increased after high doses of paraquat, peaked at 2 d postinjury, decreased sharply after 3 d and was normal by 7 d. The temporal pattern was similar to that for albumin. Cultured alveolar macrophages obtained at 4 d postinjury did not have significant increases in fibronectin release. Tissue fibronectin content increased more slowly than lavage fibronectin, peaking at 4 d postinjury, and was still elevated at 7 and 14 d postinjury. Incorporation of [35S]methionine into tissue fibronectin by lung explants obtained at different times postinjury showed a similar time course. Lung collagen content increased steadily between 4 and 14 d postinjury. We conclude that, in our model, graded degrees of lung injury and fibrosis can be produced by varying the dose of unilaterally instilled paraquat and that the increases in lavage fibronectin were related mainly to capillary permeability whereas increases in tissue fibronectin represented parenchymal synthesis. The time course of changes in lung tissue fibronectin and collagen was consistent with the proposed roles of fibronectin in tissue repair and fibrosis. The ability of our model to produce graduated degrees of lung injury and fibrosis should be useful in further studies on the pathogenesis of postinjury lung fibrosis.