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Akhil Bidani

Publications and source records attributed to Akhil Bidani.

9 recordsLinked to original sources
PubMed2003

Cell alkalosis elevates cytosolic Ca2+ in rabbit resident alveolar macrophages.

Disruption of cellular acid-base status alters the host defence functions of alveolar macrophages (m phi). These pH effects might be mediated by pH-sensitive changes in the signalling pathways of the effector functions of m phi. The present study examined the effects of intracellular pH (pH(i)) on the free cytosolic calcium concentration ([Ca(2+)](i)), an important second messenger for cell functions. [Ca(2+)](i) and pH(i) of rabbit resident alveolar m phi were measured using fluorescent dyes. With extracellular pH (pH(o)) of 7.4, the steady-state pH(i) and [Ca(2+)](i) were approx. 7.14 and 123 nM respectively. Incubation at pH(o) 6.8 caused a sustained cytosolic acidosis, but did not affect [Ca(2+)](i). Likewise, [Ca(2+)](i) was unchanged when m phi at pH(o) 7.4 were acidified using bafilomycin A(1) or sodium propionate. In contrast, [Ca(2+)](i) was markedly sensitive to cytosolic alkalosis. Exposure to NH(4)Cl at pH(o) 7.4 caused transient increases in both pH(i) and [Ca(2+)](i). The Ca(2+) response was mediated by release of intracellular Ca(2+) from thapsigargin-sensitive stores and was potentiated by capacitative entry of extracellular Ca(2+). Incubation at high pH(o) values (>7.4) produced sustained increases in pH(i) and [Ca(2+)](i). The sustained elevation of [Ca(2+)](i) was consistent with pH-sensitive inhibition of plasma-membrane Ca(2+)-ATPase. The response to high pH(o) was unaffected by blockade of L-type or receptor-operated Ca(2+) channels with nifedipine or SKF-96365, and was independent of extracellular Na(+). The findings indicate that pH impacts cytosolic Ca(2+) homoeostasis at multiple levels. The data suggest that cellular acid-base status can influence Ca(2+)-dependent signalling events in resident alveolar m phi, especially during alkaline disruptions of pH(i).

Ammonium Chloride↗
PubMed2003

Intracellular pH regulation in U937 human monocytes: roles of V-ATPase and Na+/H+ exchange.

The role of plasmalemmal V-type H+ translocating ATPase (V-ATPase) in regulation of intracellular pH (pHi) is unclear in monocytes. This study examined the plasmalemmal V-ATPase and Na+/H+ exchanger (NHE) in U937 human monocytes. The fluorescent probe 2',7'-biscarboxyethyl-5,6-carboxyfluorescein was used to monitor baseline pHi and the kinetics of pHi recovery from cytosolic acid-loads (NH4Cl prepulse). Bafilomycin A1 and 5-(N-ethyl-N-isopropyl)amiloride (EIPA) were used to delineate the activities of the H+-pump and NHE, respectively. Baseline pHi was approximately 7.13 at an extracellular pH (pHo) of 7.4 and fell progressively at lower pHo values. EIPA had no effect on baseline pHi at pHo 7.4, but caused a sustained decrement in pHi at pHo 6.0-7.0. Bafilomycin A1 had biphasic effects on baseline pHi at pHo 6.5-7.4; pHi declined approximately 0.1 units over the course of several minutes and then recovered. At pHo 6.0, bafilomycin A1 caused a sustained decrement in baseline pHi. Recovery from the bafilomycin-induced acidosis at pHo 6.5-7.4 was prevented by EIPA. Similarly, pHi recovery from NH4Cl prepulse acid-loads (pHo 7.4) was sensitive to both EIPA and bafilomycin A1. During this recovery process, Na+/H+ exchange (EIPA-sensitive component of apparent H+ efflux) was the predominant mechanism for H+ extrusion at acid-loaded pHi values < 7.0. At acid-loaded pHi values > or = 7.0, the V-ATPase (bafilomycin-sensitive component) and NHE contributed almost equally to H+ extrusion. The data provide the first evidence that plasmalemmal V-ATPase participates in pHi regulation in U937 cells. The H+-pump and NHE interacted to set baseline pHi and for pHi recovery following cytosolic acid-loading of the monocytes.

Amiloride↗
PubMed2002

Mechanical ventilatory support.

This chapter reviews the most updated knowledge regarding mechanical ventilation, its' indications and its' features both diagnostic and therapeutic. Further, the various modes of mechanical ventilation are described. The reader will also gain insight into the pathophysiology of various disease processes and the mode of ventilation that may be the most helpful in their treatment. Weaning is also discussed as well as a relatively new type of ventilation, non-invasive.

Humans↗
PubMed2002

Acute respiratory distress syndrome epidemiology and pathophysiology.

Acute respiratory distress syndrome is a devastating syndrome of lung injury following known risk factors, with a persistently high mortality. A consensus conference definition of ARDS has been adopted by clinical researchers, but potential problems remain. ARDS may represent more than one entity, and radiographic and mechanical differences between pulmonary versus extrapulmonary initiated ARDS have been described. There is increasing recognition of inflammatory mediators in the pathophysiology of acute lung injury. Surfactant abnormalities contribute to the associated lung dysfunction. A growing body of evidence supports the presence of VILI and a potential mechanism for developing MOSF, and has led to new management strategies. The importances of apoptosis to the repair process, and mechanisms that may lead to persistent fibrosis, such as the activation of the coagulant pathway with fibrin deposition, are increasingly recognized.

Animals↗
PubMed2002

Management of the acute respiratory distress syndrome.

Significant advances have occurred in the knowledge of the pathogenesis of ARDS. It is now recognized that ARDS is a manifestation of a diffuse process that results from a complicated cascade of events following an initial insult or injury. Mechanical ventilation and PEEP are still important components of supportive therapy. To avoid ventilator-associated lung injury there is emphasis on targeting ventilator management based on measurement of pulmonary mechanics. For those with resistant hypoxia and severe pulmonary hypertension adjunctive modalities, such as prone positioning and low-dose iNO, may provide important benefit. Alternative modes of supporting gas exchange, such as with partial liquid ventilation and extracorporeal gas-exchange, may serve as rescue therapies. Advances in cell and molecular biology have contributed to a better understanding of the role of inflammatory cells and mediators that contribute to the acute lung injury and the pathophysiology of the syndrome that manifests as ARDS. Based on this new understanding, the potential targets for intervention to ameliorate the systemic inflammatory response have proliferated. Examples include the cytokine network and its receptors, antioxidants, and endothelins. Apart from the challenge of testing these agents in experimental models, it seems likely that determination of the optimum combination of agents will become an equally important endeavor. A particular challenge is to develop better methods of predicting which of the many at-risk patients will go on to full-blown ARDS and MODS, thereby targeting subgroups of patients most likely to benefit from anti-inflammatory therapies. Similarly, the adverse effects of immunosuppressive therapy may be diminished by improved, perhaps molecular, techniques to detect microbial pathogens and permit differentiation between Systemic inflammatory response syndrome and sepsis.

Animals↗
PubMed2002

Plasmalemmal H+ extruders in mammalian alveolar macrophages.

The distribution of plasmalemmal V-type H+-pumps (V-ATPase) among mammalian macrophages (mvarphi) is uncertain and, hence, the functional significance of mvarphi plasmalemmal V-ATPase is unclear. This study investigated the role of V-ATPase in the regulation of intracellular pH (pH(i)) by resident alveolar mvarphi from sheep, pigs, dogs and rabbits. The fluorescent probe 2',7'-biscarboxyethyl-5,6-carboxyfluorescein was used to monitor baseline pH(i) and the rate of pH(i) recovery (dpH(i)/dt) from intracellular acid-loads (NH(4)Cl prepulse). Baseline pH(i) was 7.1-7.2. In sheep, pig and dog studies, 10 microM bafilomycin A(1) (a selective V-ATPase inhibitor) caused a rapid fall in baseline pH(i) (0.15-0.20 units); baseline values were unaffected by 0.1 mM amiloride (a Na+ transport inhibitor). V-ATPase activity (bafilomycin-sensitive component of dpH(i)/dt) was solely responsible for pH(i) recovery from intracellular acid-loads at acid-loaded pH(i) values >6.8-6.9. Na+/H+ exchange (amiloride-sensitive component of dpH(i)/dt) was detected only at acid-loaded pH(i) values <6.8. The activity of both H+ extruders increased at lower pH(i) values, albeit the Na+/H+ exchanger was more pH-sensitive than was V-ATPase. In rabbit studies, 10 microM bafilomycin A(1) and 1 mM N-ethylmaleimide (a non-specific H+-pump inhibitor) produced similar falls in baseline mvarphi pH(i), but had significantly larger effects than did the selective V-ATPase inhibitor concanamycin A (<or=15 microM). The findings suggest that plasmalemmal V-ATPase activity plays a major role in pH(i) regulation by alveolar mvarphi of sheep, pigs, dogs and rabbits.

Amiloride↗
PubMed2002

Inhibition of aquaporin-mediated CO2 diffusion and voltage-gated H+ channels by zinc does not alter rabbit lung CO2 and NO excretion.

Aquaporins (AQs) increase cell membrane CO(2) diffusivity, and it has been proposed that they may serve as transmembrane channels for CO(2) and other small gas molecules. In addition, it has been hypothesized that voltage-gated H(+) channels located on the apical membrane of the alveolar epithelium contribute to CO(2) elimination by the lung. To test whether these membrane proteins contribute to CO(2) elimination in vivo, we measured CO(2) exchange in buffer- and blood-perfused rabbit lungs before and after addition of 0.5 mM ZnCl(2), an inhibitor of both AQ-mediated CO(2) diffusion and voltage-gated H(+) channels. For comparison, red cell and lung carbonic anhydrases (CAs) were inhibited by 0.1 mM methazolamide. ZnCl(2) had no effect on CO(2) exchange when inspired CO(2) was altered between 2% and 5% in 5-min intervals. Pulmonary vascular and airway resistances were not altered by ZnCl(2). In contrast, methazolamide inhibited CO(2) exchange by 30% in buffer-perfused lungs and by 65% in blood-perfused lungs. Exhaled NO concentrations were unaffected by ZnCl(2) or by CA inhibition. Lung capillary gas exchange modelling shows that under normal resting conditions it would be necessary to reduce the alveolar-capillary membrane CO(2) diffusion capacity by >90% to lower CO(2) elimination by 10%. Therefore we conclude that red cell and lung AQs and voltage-gated H(+) channels in the alveolar epithelium contribute minimally to normal physiological CO(2) elimination.

Animals↗
PubMedDate not supplied

The effect of augmented hemodynamics on blood flow during arteriovenous carbon dioxide removal.

Arteriovenous carbon dioxide removal (AVCO2R) as an alternative treatment for acute respiratory distress syndrome uses a low resistance gas exchanger in a simple arteriovenous shunt to achieve total CO2 removal and allow lung rest. We have previously shown in our clinically relevant LD40 ovine model of smoke/burn induced acute respiratory distress syndrome that AVCO2R allows significant decreases in respiratory rate, tidal volume, peak airway pressure, and FiO2, as compared with standard mechanical ventilation. In addition, we have shown in a prospective randomized outcomes study that AVCO2R increases ventilator free days, decreases ventilator dependent days, and significantly improves survival. The purpose of this study is to further define the limits of AVCO2R through hemodynamic augmentation and evaluation of peak end expiratory pressure (PEEP). Administration of an alpha agonist (phenylephrine) and a beta agonist (isoproterenol) increased mean arterial pressure (MAP) and cardiac output (CO), respectively. MAP increases ranged from 2.4% to 94.4% and CO increases ranged from 33% to 146%. Phenylephrine caused elevations in MAP (2.4-94.4%) and AVCO2R flow (9-67%), and CO never decreased more than 10%. Isoproterenol administration increased CO (33-146%), decreased MAP (9-54%), and decreased AVCO2R flow (11-42%). In a second group, PEEP was increased stepwise from 0 (baseline) to 20 cm H2O. Increasing PEEP did not result in significant hemodynamic changes (< 10% change from baseline PEEP) for MAP, CO, or AVCO2R flow. In conclusion, alpha agonist administration increased AVCO2R blood flow, whereas beta agonist administration decreased MAP and AVCO2R blood flow, despite CO elevation. Various levels of PEEP are well tolerated and thus allow a range of options during AVCO2R.

Adrenergic alpha-Agonists↗