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E R Jacobs

Publications and source records attributed to E R Jacobs.

33 records · Page 2Linked to original sources
PubMed1993

pH-induced calcium transients in type II alveolar epithelial cells.

Although both intracellular pH (pHi) and intracellular Ca2+ concentration ([Ca2+]i) are highly regulated and have important metabolic effects in alveolar epithelial cells, little is known about the interrelationship between these two ions in alveolar epithelial cells. The present study examined changes in [pH]i and [Ca2+]i in isolated alveolar epithelial cells using the fluorescent dyes SNARF-1 and fura-2. Basal pHi values in freshly isolated and cultured alveolar epithelial cells were 7.27 and 7.24, respectively. Resting [Ca2+]i values in freshly isolated cells (53 +/- 5 nM) were lower than those in cultured type II cells (107 +/- 21 nM). pHi increased rapidly after addition of 25 mM NH4Cl in both cultured and freshly isolated cells and then decreased back toward baseline over the following 10 min. The rise in pHi was associated with a transient increase in [Ca2+]i. Resuspension of cells in an NH4Cl-free solution resulted in rapid intracellular acidification, which recovered over the subsequent 10 min. Removal of sodium or addition of 1 mM amiloride to the external solution slowed the rate of recovery from intracellular acidification, consistent with the participation of Na(+)-H+ exchanger in this process. In freshly isolated cells, [Ca2+]i increased following acidification and then decreased as the cells recovered from an acid load. In cultured cells, [Ca2+]i also increased following acidification but then remained elevated over the subsequent 10 min. The recovery of [Ca2+]i toward baseline values in fresh cells following acidification was dependent on the presence of external sodium. These data demonstrate that both increases and decreases in pHi of alveolar epithelial cells are associated with increases in [Ca2+]i and suggest that some of the metabolic effects of altering pHi may be secondary to increases in [Ca2+]i. The dependency of [Ca2+]i recovery following acidification on external sodium raises the possibility that freshly isolated type II cells have Na(+)-Ca2+ exchangers that contribute to the regulation of [Ca2+]i.

Amiloride↗
PubMed1990

Mechanisms of potassium channel block in rat alveolar epithelial cells.

Block of inactivating delayed rectifier K+ currents was studied in rat alveolar epithelial cells in primary culture using the whole-cell configuration of the gigohm-seal voltage-clamp technique. Charybdotoxin was the only blocker studied which did not alter K+ current kinetics; it produced a simple block (K1 approximately 1 nM) which appeared to be independent of voltage or channel state (open, closed or inactivated). Tetraethylammonium slowed inactivation of K+ currents, consistent with the notion that blocked channels cannot inactivate. Verapamil and methoxyverapamil produced time-, voltage- and concentration-dependent "inactivation" or block of open channels during depolarizing pulses, with negligible block of closed channels at negative holding potentials. Capsaicin, chlorpromazine, phencyclidine, quinidine and tetrahydroaminoacridine both increased the rate of inactivation and decreased the peak K+ current. These characteristics suggest that both open and closed channels can be blocked, but that open channels are blocked preferentially. Nifedipine, like most other blockers, increased the rate of K+ current decay, but, unlike other blockers, resulted in two distinct kinetic components of current decay under some conditions. Because nifedipine is uncharged, the voltage and time-dependence of its block cannot be ascribed to a traditional ionic blockade mechanism. Mechanisms of K+ channel block are compared with block of Ca++ channels by calcium "antagonists" and block of Na+ channels by local anesthetics. Interactions between gating kinetics and K+ channel blockade seem to be the rule rather than the exception.

Animals↗
PubMed1989

Ion channels in the metabolic regulation of respiratory cells.

This article has focused on the characteristics of ion channels in cells of the respiratory system. Ion channels and their role in transepithelial fluid movement are best understood in tracheal epithelial cells. The bulk of the evidence indicates that a Cl- channel abnormality is etiologically involved in CF. In other cell types, such as isolated type II alveolar epithelial and vascular endothelial cells, ion channels have been described, but their functional significance is only incompletely understood. Finally, the majority of cells in the lungs has yet to be studied electrophysiologically. It is hoped that eventually studies of channel properties may enable investigators to determine how the channels affect cell function.

Bronchi↗
PubMed1988

Potassium currents in rat type II alveolar epithelial cells.

1. Type II alveolar epithelial cells isolated from adult rats and grown in primary culture were studied using the whole-cell configuration of the gigohm-seal voltage clamp technique. 2. The average specific capacitance of type II cells was 2.5 microF/cm2, suggesting that type II cell membranes in vitro are irregular, with an actual area more than twice the apparent area. 3. Most type II cells have time- and voltage-dependent outward currents carried by potassium ions. Potassium currents activate with a sigmoid time course upon membrane depolarization, and inactivate during maintained depolarization. The average maximum whole-cell K+ conductance was 1.6 nS. 4. Two distinct types of K+-selective channels underlie outward currents in type II cells. Most cells have currents resembling delayed rectifier K+ currents in skeletal muscle, nerve and immune cells. A few cells had a different type of K+ conductance which is more sensitive to block by tetraethylammonium ions, has faster 'tail currents', and activates at more positive potentials. 5. In some experiments, individual type II cells were identified by staining with phosphine, a fluorescent dye which is concentrated in lamellar bodies. Both types of K+ channels were seen in type II cells identified with this dye. 6. Phosphine added to the bathing solution reversibly reduced K+ currents and shifted K+ channel activation to more positive potentials. Excitation of phosphine to fluoresce reduced irreversibly K+ currents in type II cells. The usefulness of phosphine as a means of identifying cells for study is discussed.

Action Potentials↗
PubMed1986

Clinical indicators in sepsis and septic adult respiratory distress syndrome.

Sepsis and septic ARDS remain clinical problems of great significance because of the numbers of patients affected each year and the high mortality associated with development of the syndrome. The standard therapies for these conditions, judicious antibiotic administration and supportive care, continue to be the mainstays of treatment for these patients, but mortality even with optimal conventional therapy is between 50% and 90% for septic ARDS. The mortality for an individual patient may be anticipated to be substantially higher or lower than these average reported values, based on the presence or absence of several clearly identified risk factors, such as advanced age, shock, evidence of multiorgan system failure, and others discussed above. Similarly, the likelihood that the septic patient will develop ARDS is increased by the appearance of shock and thrombocytopenia. Two therapies that are used extensively in the intensive care unit today--corticosteroid administration and PEEP--have not been shown to reduce the overall mortality of sepsis or septic ARDS. Newer therapeutic modalities, designed to protect against or reverse cardiovascular consequences of sepsis, reduce the incidence of multiorgan system failure, and diminish the high incidence of uncontrolled infections in these patients, are needed; investigations of these interventions are in progress.

Adrenal Cortex Hormones↗
PubMed1986

Therapeutic implications of acute lung injury.

Although there are no specific therapies for septic shock or acute lung injury that have proven efficacy in humans, a growing understanding of mechanisms of tissue injury has suggested interventions that may prevent or treat this injury. These therapies range from immunization against the glycopolysaccharide core of endotoxin to cyclooxygenase inhibitors to specific oxygen radical scavengers. Each of these treatments is effective in ameliorating at least one of the pathophysiologic manifestations of acute lung injury, although the effect of these agents in the prevention of the sequelae of fibrosis is unknown. Interaction between several factors and mediators is likely necessary for the development of acute lung injury. It is hoped that with additional knowledge regarding mechanisms of injury gained through basic science and clinical research, we can apply definitive therapy that may salvage patients who now die with sepsis and acute lung injury.

Blood Platelets↗
PubMed1985

Immunoglobulin G-induced single ionic channels in human alveolar macrophage membranes.

While it is well known that the engagement of IgG Fc receptors on the macrophage surface triggers a number of cellular responses, including particle ingestion, secretion, and respiratory burst activity, the mechanism of signal transmission following ligand binding remains poorly understood. To acquire more data in this area, we studied the electrical properties of the macrophage membrane and its response to oligomeric immunoglobulin G (IgG) using the patch-clamp technique on human alveolar macrophages that were obtained by bronchoalveolar lavage and maintained in short-term tissue culture. The results showed that cell resting potentials, as determined from whole-cell tight seal recordings, increased from -15 mV on the day of plating to -56 mV after the first day in culture and remained stable at this hyperpolarized level. Macrophages revealed an input resistance of 3.3 G omega, independent of age in culture. Extracellular application of heat-aggregated human IgG to cells voltage-clamped at -70 mV resulted in peak inward currents of approximately 470 pA. We identified an IgG-dependent, nonselective channel in both cell-attached and isolated membrane patches, with a unitary conductance of approximately 350 pS and a predominant subconductance level of 235 pS in symmetrical NaCl solutions. Single channel open times were observed to be in the range of seconds and, in addition, were dependent upon membrane voltage. Channel opening involved transitions between a number of kinetic states and subconductance levels. Channel events recorded in cell-attached patches showed characteristic exponential relaxations, which implied a variation in membrane potential as a result of a single ion channel opening. These data suggest that the IgG-dependent nonselective cation channel that we have characterized may provide the link between Fc receptor engagement and subsequent cellular activation.

Adult↗
PubMed1984

Research on ibuprofen for sepsis and respiratory failure.

According to an experimental study in 26 dogs, ibuprofen reversed the hypotension, increased the cardiac index, prevented the acidosis associated with endotoxic shock, and apparently improved survival. In animals given endotoxin followed by ibuprofen, an initial decrease in systemic blood pressure subsequently recovered to 150.2 +/- 4.1 mm Hg in 120 minutes (p less than 0.001). Cardiac index increased in ibuprofen-treated animals (2.3 +/- 0.28 1/m2 per minute), compared with animals given endotoxin alone (1.0 +/- 0.09 1/m2 per minute) by termination of the experiment. In addition, although arterial pH decreased to 7.18 +/- 0.03 by 120 minutes in animals given only endotoxin, final pH was 7.36 +/- 0.01 in the ibuprofen-treated group.

Animals↗
PubMed1984

Protection of myocardial function during endotoxin shock by ibuprofen.

We have concluded that Ibuprofen, a cyclooxygenase inhibitor with high specificity for the preferential blockage of thromboxane synthetase, significantly improves arterial blood pressure, cardiac index, and arterial pH during endotoxin shock in dogs (J. Clin. Invest. 70:536, 1982). This study was undertaken to determine whether Ibuprofen (25 mg/kg i.v.) administered 20 min prior to endotoxin (2 mg/kg i.v.) is able to overcome the depressed ability of cardiac microsomes to actively sequester calcium after 2 hrs of endotoxin shock. Results indicate that microsomes isolated from hearts of animals pretreated with Ibuprofen and then given endotoxin are able to sequester calcium at rates similar to microsomes isolated from control hearts. Microsomes isolated from hearts of animals in endotoxin shock without Ibuprofen show the anticipated depression of calcium sequestering ability. The improved ability of microsomes from the hearts of animals pretreated with Ibuprofen to sequester calcium is the result of normal Ca+2-Mg+2 ATPase activity in the microsomal membrane. We conclude that Ibuprofen protects against the detrimental hemodynamic derangements of endotoxin induced shock in the dog, and thereby also improves cardiac subcellular calcium transport; the factor regulating contractility. Ibuprofen may warrant evaluation as a protective agent to be used prophylactically in high risk cases of endotoxemia.

Animals↗
PubMed1983

Mediators of septic lung injury.

Septic pulmonary injury remains a significant cause of morbidity and mortality among hospitalized patients today and is likely to increase in prevalence as advances in medical technology allow the salvage of more critically ill and immunocompromised hosts. Treatment of the host's underlying disease and even of the infection itself has appeared to redeem septic patients only to have them succumb in increasing numbers to the pulmonary injury reaction. Our understanding of the mechanisms and mediators of lung dysfunction in sepsis is in a rapidly expanding phase. Currently we recognize the contributions of several blood elements, lipids, and peptides to pulmonary injury, although the relative importance and points of interaction and interdependence of these mediators remain to be established. It is hoped that a more complete understanding of the process of pulmonary injury in sepsis will suggest effective means of intervention at a stage in which damage may be reversed or minimized.

Animals↗
PubMed1982

Ibuprofen in canine endotoxin shock.

The participation of prostaglandins in the physiologic alterations of endotoxin shock has been well established with the aid of prostaglandin synthetase inhibitors. Our study was designed to investigate the potential of ibuprofen, a highly specific cyclooxygenase inhibitor, to reverse the hemodynamic and acid base abnormalities of canine endotoxin shock. Mean blood pressure fell to 49.8 +/- 6.6 mm Hg in dogs given endotoxin by 5 min after injection, and remained below 83 mm Hg for the duration of the 120-min observation period. In animals given endotoxin followed by ibuprofen, a similar initial drop of systemic blood pressure was seen, but it subsequently recovered to 150.2 +/- 4.1 mm Hg by 120 min (P less than 0.001). Cardiac index increased in animals given ibuprofen (2.3 +/- 0.28 liter/m2 per min) compared with animals given endotoxin alone (1.0 +/- 0.09 liter/m2 per min) by termination of the experiment. The arterial pH dropped in endotoxin treated animals to 7.18 +/- 0.03 by 120 min. Ibuprofen prevented the acidosis, the final pH in ibuprofen and endotoxin treated animals measuring 7.36 +/- 0.01. We conclude that ibuprofen protects against the hypotension, acidosis, and depression of cardiac index of canine endotoxin shock.

Animals↗