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Biomedical subjects

D H Ingbar

Publications and source records attributed to D H Ingbar.

54 records · Page 3Linked to original sources
PubMed1994

Alveolar epithelial cells regulate the induction of endothelial cell apoptosis.

Mesenchymal cell apoptosis is important during development, tissue homeostasis, and repair. We sought to determine whether type II alveolar epithelial cells influence mesenchymal cell apoptosis, using the model of tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis of endothelial cells. Apoptosis was quantified by morphology and confirmed by electrophoretic DNA size analysis. Endothelial cells exposed to 20 ng/ml of TNF-alpha for 16 h exhibited apoptosis in 14.4 +/- 1.4% (SE) of the cells, whereas serum-free conditioned media (CM) from primary cultures of rat type II cells reduced TNF-alpha-induced apoptosis by 52% to 7.5 +/- 0.9% (P < 0.01). Flow cytometric analysis of subdiploid DNA content per cell also showed that CM reduced the percentage of cells with TNF-alpha-induced DNA degradation by 48 +/- 1.7%. The protective effect of CM was concentration dependent and also was effective across a range of TNF concentrations. This CM factor was trypsin sensitive and stable at 65 degrees C for 1 h. It bound to a Mono-Q anion-exchange resin, eluting in a discrete peak at 1.18 M NaCl and pH 8.5. Therefore alveolar type II cells release a heat-stable peptide(s) that protects endothelial cells against apoptosis induced by TNF. Our results suggest that alveolar epithelial cells regulate the response of mesenchymal cells to factors that induce apoptosis during injury and repair.

Animals↗
PubMed1994

Diagnosis and management of acute lung injury.

Severe acute lung injury, also known as the adult respiratory distress syndrome (ARDS), is a dynamic and explosive clinical syndrome which exacts a mortality of approximately 50%. The criteria for the diagnosis of severe acute lung injury include five principal elements: hypoxemia despite high concentrations of supplemental oxygen, diffuse pulmonary infiltrates on chest radiographs, decreased lung compliance, appropriate antecedent history, and the absence of congestive heart failure. Identifying an appropriate antecedent history requires consideration of a diverse group of etiologies which may injure alveolar structures via either the air-lung or blood-lung interface. The management of patients with acute lung injury should be approached with four principal goals: (1) cardiopulmonary resuscitation and stabilization; (2) rapid identification and elimination of the cause of lung injury; (3) achieving adequate tissue oxygen delivery and support of other end-organs; and (4) prevention, recognition, and aggressive treatment of any complications that develop during the course of therapy. Recent observations have suggested that conventional methods of positive-pressure ventilation may indirectly injure alveolar tissue, thereby perpetuating lung injury. Furthermore, the optimal use of fluid and hemodynamic support remains controversial. Thus, controlled clinical trials are necessary to develop oxygenation, ventilatory, and hemodynamic support strategies which optimize recovery and minimize further injury and to define the role of newer pharmacologic agents in the prevention and treatment of acute lung injury.

Adult↗
PubMed1994

Massive hemoptysis. Assessment and management.

The first priorities in treating the patient with massive hemoptysis are to maintain the airway, optimize oxygenation, and stabilize the hemodynamic status. The major question to be answered is whether or not the patient should be intubated for better gas exchange, suctioning, and protection from sudden cardiorespiratory arrest. If the bleeding site is known, the patient should be placed with the bleeding lung in the dependent position. Once stabilization is accomplished, diagnostic and therapeutic interventions should be promptly performed because recurrent bleeding occurs unpredictably. Early bronchoscopy, preferably during active bleeding, should be performed with three goals in mind: to lateralize the bleeding side, localize the specific site, and identify the cause of the bleeding. In those patients with lateralized or localized persistent bleeding, immediate control of the airway may be obtained during the procedure with topical therapy, endobronchial tamponade, or unilateral intubation of the nonbleeding lung. If bleeding continues but the side of origin is uncertain, lung isolation or use of a double-lumen tube is reasonable, provided that the staff is skilled in this procedure. If the bleeding cannot be localized because the rate of hemorrhage makes it impossible to visualize the airway, emergent rigid bronchoscopy or emergent arteriography is indicated. Arteriography and embolization should be used emergently for both diagnosis and therapy in those patients who continue to bleed despite endobronchial therapy. Emergent surgical intervention should be considered in operative candidates with unilateral bleeding when embolization is not available or not feasible, when bleeding continues despite embolization, or when bleeding is associated with persistent hemodynamic and respiratory compromise. For patients in whom bleeding has ceased or is decreased, emergent intervention may not be necessary. If the bleeding site has been localized or lateralized with early bronchoscopy, recurrent bleeding can be managed more confidently and rapidly. The cause of bleeding can be determined at bronchoscopy in patients with endobronchial adenomas, carcinomas, foreign bodies, or broncholiths. If no diagnosis is obtained at bronchoscopy, elective angiography of the bronchial and, if necessary, the pulmonary vasculature is reasonable. The precise timing and nature of the further evaluation are dictated by the suspected underlying pathologic process and the clinical condition of the patient. Surgery is the most definitive form of therapy for patients with hemoptysis because it removes the source of bleeding. Whether to proceed with elective surgery in patients with a major bleed that stops or one that is controlled angiographically is a difficult decision. Little data are available to assist in this decision, even for specific diseases, such as bronchiectasis. Similarly, the long-term course of patients treated with endobronchial tamponade or topical therapy is unknown. For patients with inoperable disease, limited reserve, or bilateral progressive disease, embolization frequently controls bleeding for prolonged periods.(ABSTRACT TRUNCATED AT 400 WORDS)

Diagnosis, Differential↗
PubMed1993

Role of mesenchymal cell death in lung remodeling after injury.

Repair after acute lung injury requires elimination of granulation tissue from the alveolar airspace. We hypothesized that during lung repair, signals capable of inducing the death of the two principal cellular elements of granulation tissue, fibroblasts and endothelial cells, would be present at the air-lung interface. Bronchoalveolar lavage fluid obtained from patients during lung repair induced both fibroblast and endothelial cell death, while fluid obtained at the time of injury or from patient controls did not. The mode of cell death for endothelial cells was apoptosis. Fibroblast death, while morphologically distinct from necrosis, also differed from typical apoptosis. Only proliferating cells were susceptible to the bioactivities in lavage fluid, which were trypsin sensitive and lipid insoluble. Histological examination of lung tissue from patients after lung injury revealed evidence of apoptotic cells within airspace granulation tissue. Our results suggest that cell death induced by peptide(s) present at the air-lung interface may participate in the remodeling process that accompanies tissue repair after injury.

Acute Disease↗
PubMed1992

A universal precautions monitoring system adaptable to any health care department.

The Occupational Safety and Health Administration has proposed monitoring employee compliance with universal precautions, as recommended by the Centers for Disease Control. Our respiratory care department, following a four-step system development plan, has developed and implemented a universal precautions monitoring system that is easy to adapt to any health care department. The results from monitoring can be used for educational planning, quality assurance purposes, and employee performance reviews.

Cooperative Behavior↗
PubMed1991

Upregulation of rat lung Na-K-ATPase during hyperoxic injury.

A major function of the alveolar epithelium is to keep the airspace free of fluid and preserve gas exchange. Since Na-K-ATPase is believed to be important in this process, we hypothesized that Na-K-ATPase in the rat lung would increase in response to acute lung injury with pulmonary edema. Na-K-ATPase localization, mRNA expression, and protein levels were determined in hyperoxic lung injury. Adult male rats were exposed to greater than 97% oxygen for 60 h followed by recovery in room air. At 60 h of hyperoxia, the wet-to-dry lung weights increased, consistent with edema. Within the alveolar capillary region, the sodium pump remained localized to the type II cell basolateral membrane by immunocytochemistry. By Northern blot analysis, the level of total lung mRNA expression of the alpha 1- and beta-subunits of Na-K-ATPase increased three- to fourfold during hyperoxia compared with unexposed rats. Total lung Na-K-ATPase membrane protein, visualized with a Western blot technique, appeared to increase by 24 h of hyperoxic insult when compared with levels in unexposed animals. The increase in sodium pump gene expression that occurs during hyperoxic insult, followed by an increase in sodium pump membrane protein, suggests that type II cells increase their Na-K-ATPase synthesis as an early response to pulmonary edema and/or hyperoxia.

Animals↗
PubMed1989

Polarized distribution of Na+,K+-ATPase in giant cells elicited in vivo and in vitro.

Giant cell formation was analyzed to determine whether it results in the high level of Na+,K+-ATPase expression that characterizes multinucleated cells such as osteoclasts. Giant cells and fusing alveolar macrophages were subjected to morphological, immunological, and biochemical studies. Both subunits of the Na+,K+-ATPase were found to be present on the plasma membrane of giant cells. Their localization was restricted to the non-adherent domain of the cell surface. Dynamic studies of giant cell differentiation demonstrated that on culture and/or multinucleation, an increase in sodium pump alpha-subunit synthesis occurred and led to a high level of expression of Na pumps. Conversely, the adherent plasma membrane of giant cells was enriched in a lysosomal membrane antigen. This study demonstrates that culture and/or multinucleation induces a significant increase in the expression of sodium pumps. The polarized distribution of these pumps and of a lysosomal component suggests that fusing macrophages undergo biochemical and morphological alterations which prepare them for a new and specialized function in chronic inflammatory reactions. Giant cells may offer a suitable model system to study the differentiation of other related multinucleated cells, such as osteoclasts.

Animals↗
PubMed1988

Acute respiratory failure.

Respiratory failure is a common problem in the patient with cancer. Many of these patients require intubation and treatment in an intensive care unit. Expeditiously determining the cause of the respiratory failure and treating it appropriately is mandatory. In addition, understanding the reason for respiratory failure permits rational determination of the aggressiveness of therapy.

Acute Disease↗
PubMed1986

Repopulation of a human alveolar matrix by adult rat type II pneumocytes in vitro. A novel system for type II pneumocyte culture.

This paper describes the preparation of lung acellular alveolar matrix fragments and culture of rat type II pneumocytes directly on the alveolar epithelial basement membrane, thereby permitting study of the effect of lung basement membrane on the morphology and function of type II cells. Collagen types I, III, IV and V, laminin and fibronectin were located by immunofluorescence in the lung matrix with the same patterns as those described for the normal human lung. Transmission electron microscopy (TEM) of the fragments revealed intact epithelial and endothelial basement membranes. The matrix maintained the normal three-dimensional alveolar architecture. Glycosaminoglycans were still present by Alcian Blue staining. Isolated adult rat type II pneumocytes cultured on 150 micron thick fragments of acellular human alveolar extracellular matrix undergo gradual cytoplasmic flattening, with loss of lamellar bodies, mitochondria, and surface microvilli. These changes are similar to the in vivo differentiation of type II pneumocytes into type I pneumocytes. The type II pneumocyte behaviour on the lung epithelial basement membrane contrasted sharply with that of the same cell type cultured on a human amnionic basement membrane. On the latter surface the cells retained their cuboidal shape, lamellar bodies and surface microvilli for up to 8 days. These observations suggest that the basement membranes from different organ systems exert differing influences on the morphology and function of type II pneumocytes and that the alveolar and amnionic basement membranes may have differing three-dimensional organizations. The technique of direct culture of type II cells on the lung basement membrane provides a useful tool for studying the modulating effect of the basement membrane on alveolar epithelial cells.

Basement Membrane↗
PubMed1986

An in vitro model for polymorphonuclear-leukocyte-induced injury to an extracellular matrix. Relative contribution of oxidants and elastase to fibronectin release from amnionic membranes.

Alteration of the extracellular matrix by inflammatory cells is believed to be important in both lung injury and the subsequent restoration of lung architecture. Here we describe the results of the interaction between an acellular human amnionic membrane model and stimulated human polymorphonuclear neutrophils (PMN) in vitro. Polymorphonuclear neutrophil suspensions were placed on one surface of the amnion, and either the chemotactic peptide FMLP or the cell membrane activator phorbol myristate acetate (PMA) was placed on the opposite side of the amnion. Stroma and basement membrane sides of the amnion were separately exposed to the PMN. The PMN suspension was removed and centrifuged, and the supernatant was assayed for superoxide anion (O2-.) and for elastase activity. Injury to the acellular amnion was evaluated by transmission electron microscopy and by measurement of fibronectin (FN) released from the membrane matrix. Although both stimulants cause a concentration-dependent release of O2-., only PMA stimulated elastase release. These effects were similar when either the stroma or the basement membrane side was exposed to PMN. PMA-stimulated cells and supernatants from PMA-stimulated cells caused solubilization of membrane at different incubation times. Electron microscopy confirmed the disruption of the basement membrane of the amnion by PMA-stimulated PMN. Oxidant scavengers (SOD and catalase) did not prevent matrix degradation, and elastase inhibition by a specific chloromethylketone inhibitor diminished FN release on both sides of the amnion by activated PMN supernatants, but only on the basement membrane side by intact PMN. We conclude that in this model, elastase rather than oxygen radicals solubilizes FN from the matrix.

Amnion↗
PubMed1986

Pulmonary sequelae and lung repair in survivors of the adult respiratory distress syndrome.

The high in-hospital mortality of ARDS has not diminished over the past 10 years, despite improvements in supportive intensive care. Much of the mortality arises from infections, particularly sepsis and pneumonia, and from organ failure, especially kidney failure. The rapid advances in understanding the interlocking pathophysiologic mechanisms of ARDS have not yet been translated into therapeutic trials of new methods for diminishing the injury or for stimulating normal repair. In part, this is because it is difficult to predict which high-risk patients will develop ARDS and then intervene early in the injury process. Patients in whom the risk for ARDS is extremely high have a very high mortality even without ARDS, thereby making efficacy of an early or prophylactic therapy quite difficult to prove. In spite of severe pathologic abnormalities, including fibrosis, early in the course of ARDS, most survivors return to almost normal pulmonary function. The few cases that have been studied with serial biopsies demonstrate resolution of fibrosis. This amazing recovery poses many fascinating questions about how the lung repairs itself. Given the heterogeneous causes of ARDS and the large number of structural, cellular, and biochemical abnormalities described, one can postulate that any one of numerous factors is important in normal repair. Most promising of these are the degree of basement membrane damage, the control of type II cell proliferation and differentiation, the control of collagen synthesis, the anatomic localization of fibrosis, and the control of collagenase action. These interactions of epithelial and mesenchymal tissues probably recreate the process of lung development in the injured adult lung. At a clinical level, the role of oxygen toxicity remains a significant issue. Oxygen acting as an oxidant may be partially responsible for the small airways disease seen in approximately one quarter to one third of survivors. The mortality data stress the need for better ways of preventing and diagnosing lung infections. Better definition of the clinical factors that put survivors at risk for persistent loss of lung function is also needed, and could define a subgroup in which trials of agents designed to improve repair would be most worthwhile. More information about the long-term pathologic course, though difficult to obtain, would also be very important. Perhaps some registry of ARDS survivors would permit closer follow-up and make available more late autopsy pathology when these people die of other causes. The rapid time course of ARDS provides an ideal testing ground for agents designed to either decrease lung injury or stimulate repair.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
PubMed1985

Pathophysiology and treatment of sleep apnea.

The sleep apnea syndromes have attracted the interest of physicians and scientists in many different disciplines because the disorders involve the physiology of sleep, the control of respiration, the function of the upper airway, and the clinical sequelae upon cardiac, pulmonary, and psychological function. Over the eight years since this subject was last reviewed here (1), the pathophysiology of obstructive sleep apnea has become better understood. A variety of new treatments are now available. However, our clinical knowledge of the syndrome and its natural history have changed little. The high prevalence of these syndromes and related disorders such as snoring is only beginning to be apparent. This chapter reviews current understanding of these syndromes, with particular emphasis on recent advances, and highlights questions for future investigation. First, we consider normal upper airway function and the control of breathing during sleep. Then, we apply this information to a consideration of the pathophysiology, clinical features, and treatment of sleep apnea syndromes.

Airway Resistance↗
PubMed1984

Bleomycin hydrolase activity in pulmonary cells.

The metabolism of bleomycin (BLM) A2 by BLM hydrolase in the 105,000 X g supernatant fraction of homogenates obtained from freshly isolated and cultured pulmonary cells was assayed by high-pressure liquid chromatography. BLM A2 was converted solely to the less toxic desamido metabolite by the cytosol from isolated rabbit and bovine alveolar and interstitial macrophages, cultured rabbit and bovine pulmonary fibroblasts and cultured rabbit pulmonary artery endothelial cells. The BLM hydrolase activity in the cytosol from cultured rabbit fibroblasts had an apparent Km of 700 microM and Vmax of 33 nmol/hr/mg protein. The rate of BLM dA2 formation found with the cytosol of cultured rabbit pulmonary artery endothelial cells and pulmonary fibroblasts was 3 to 5 times greater per cell than that from the cytosol of rabbit alveolar and interstitial macrophages. Freshly isolated rabbit type II pneumocytes and bovine pulmonary artery endothelial cells grown in culture had undetectable levels of this inactivating enzyme activity. The expression of BLM hydrolase activity in rabbit pulmonary fibroblasts was stable for at least five passages in culture and was not significantly different over wide cell densities in culture. These data suggest that heterogeneity in the cellular distribution of BLM hydrolase activity exists in lungs. High levels of BLM hydrolase activity in the pulmonary endothelium or fibroblasts of some species may have an important role in determining the toxicity of BLM to the lungs.

Animals↗
PubMed1975

The effect of food deprivation of the peripheral metabolism of thyroxine in rats.

Starvation depresses thyroid gland function. In addition, the peripheral turnover of thyroxine (T4) is reduced, in part due to decreased fecal elimination of T4. The present studies were performed to determine if starvation also affects the deiodinative pathway for T4 degradation. Rats were isotopically equilibrated with daily injections of exogenous [131-I]T4 while endogenous thyroidal T4 secretion and concentration of iodide were blocked with KCl04. Following a period of equilibration, either complete or 50% food deprivation was imposed on half the animals. Within 48 h of starvation, the serum T4 concentration of the fully starved rats doubled and remained high throughout. A marked decrease in fecal excretion of T4 was partially responsible for the increase. In spite of variability in the quantity of urinary 131-I excreted, the dieodinative clearance was consistently reduced. These effects were readily reversible upon resumption of normal feeding. Similar though less severe changes were observed in the half-fed rats. In both fully and partially-starved animals, the decreased dieodinative clearance in the face of increased serum T4 levels indicates a significant impairment of peripheral deiodination by some as yet unknown mechanism. In contrast, normal rats equilibrated with doses of T4 sufficient to increase serum T4 levels exhibit increased urinary clearance of iodide derived from T4. Thus the increased serum T4 levels are a consequence of impairment of the deiodinative pathway by starvation as well as decreased fecal T4 excretion. Clearly, voluntary alterations in food consumption must be controlled for differences between groups during experimental studies of T4 utilization.

Animals↗