PubMed Health⌕ Search

Biomedical subjects

Aaron B Waxman

Publications and source records attributed to Aaron B Waxman.

9 recordsLinked to original sources
PubMed2007

Plasma gelsolin is a marker and therapeutic agent in animal sepsis.

OBJECTIVE: Plasma gelsolin is a circulating actin-binding protein that serves a protective role against tissue injuries. Depletion of plasma gelsolin in systemic inflammation may contribute to adverse outcomes. We examined the role of plasma gelsolin in animal models of sepsis. DESIGN: Animal and laboratory experiments. SETTING: Academic research laboratory. SUBJECTS: Adult male mice. INTERVENTIONS: Mice subjected to endotoxin or cecal ligation and puncture (CLP) were treated with exogenous plasma gelsolin or placebo. MEASUREMENTS AND MAIN RESULTS: We document the depletion of plasma gelsolin (25-50% of normal) in murine models of sepsis associated with the presence of circulating actin within 6 hrs of septic challenge. Repletion of plasma gelsolin leads to solubilization of circulating actin aggregates and significantly reduces mortality in endotoxemic mice (survival rates were 88% in the gelsolin group vs. 0% in the saline group, p < .001) and in CLP-challenged mice (survival rates were 30% in the gelsolin group vs. 0% in the saline group, p = .001). Plasma gelsolin repletion also shifted the cytokine profile of endotoxemic mice toward anti-inflammatory (plasma interleukin-10 levels were 205 +/- 108 pg/mL in the gelsolin group vs. 39 +/- 29 pg/mL in the saline group, p = .02). CONCLUSIONS: We propose that circulation of particulate actin is a marker for sepsis-induced cell injury, that plasma gelsolin has a crucial protective role in sepsis, and that gelsolin replacement represents a potential therapy for this common lethal condition.

Actins↗
PubMed2006

DNA damage induced by hyperoxia: quantitation and correlation with lung injury.

Inspired oxygen, an essential therapy for cardiorespiratory disorders, has the potential to generate reactive oxygen species that damage cellular DNA. Although DNA damage is implicated in diverse pulmonary disorders, including neoplasia and acute lung injury, the type and magnitude of DNA lesion caused by oxygen in vivo is unclear. We used single-cell gel electrophoresis (SCGE) to quantitate two distinct forms of DNA damage, base adduction and disruption of the phosphodiester backbone, in the lungs of mice. Both lesions were induced by oxygen, but a marked difference between the two was found. With 40 h of oxygen exposure, oxidized base adducts increased 3- to 4-fold in the entire population of lung cells. This lesion displayed temporal characteristics (a progressive increase over the first 24 h) consistent with a direct effect of reactive oxygen species attack upon DNA. DNA strand breaks, on the other hand, occurred in < 10% of pulmonary cells, which acquired severe levels of the lesion; dividing cells were preferentially affected. Characteristics of these cells suggested that DNA strand breakage was secondary to cell death, rather than a primary effect of reactive oxygen species attack on DNA. By analysis of IL-6- and IL-11-overexpressing transgenic animals, which are resistant to hyperoxia, we found that DNA strand breaks, but not base damage, correlated with acute lung injury. Analysis of purified alveolar type 2 preparations from hyperoxic mice indicated that strand breaks preferentially affected this cell type.

Animals↗
PubMed2006

Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension: a pilot study.

STUDY OBJECTIVES: We assessed the efficacy of bosentan in transitioning from prostacyclin infusions in patients with pulmonary arterial hypertension (PAH). METHODS: Twenty-two PAH patients were recruited from five PAH centers if they had been clinically stable while receiving therapy with IV epoprostenol or subcutaneous treprostinil for at least 3 months. Patients were observed in an open-label prospective trial while bosentan was added to therapy, and then epoprostenol or treprostinil were tapered after 2 months. RESULTS: Ten of the 22 patients were transitioned off prostacyclin infusion therapy after a mean (+/- SEM) duration of 6.1 +/- 1.2 months. Of those patients, seven patients have continued not receiving prostacyclin infusion therapy for a mean duration of 17.7 +/- 5.3 months, with no significant changes in pulmonary artery (PA) pressure estimated by echocardiography, World Health Organization (WHO)/New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD), or Borg dyspnea score. The conditions of three patients deteriorated, necessitating the resumption of prostacyclin therapy, and two patients subsequently died. Twelve patients failed to transition or even lower the prostacylin infusion rate and had worsening of their WHO/NYHA functional class and estimated systolic PA pressures, and had a trend toward deterioration in their mean 6MWD (294 +/- 41 to 198 +/- 34 m, respectively; p = 0.2). Of these, two patients subsequently died. The baseline characteristics of those who transitioned successfully vs those who transitioned unsuccessfully were a lower prostacyclin infusion rate, and less severe elevations in the mean and estimated systolic PA pressures. CONCLUSION: Transitioning from therapy with prostacyclin to bosentan is possible in some PAH patients, mainly in those receiving lower prostacyclin doses and having less pulmonary hypertension at baseline. Careful patient selection and close interim monitoring is needed because the conditions of patients can deteriorate, and they may not respond to the resumption of therapy with prostacyclin.

Administration, Oral↗
PubMed2005

Roundtable debate: Controversies in the management of the septic patient--desperately seeking consensus.

Despite continuous advances in technologic and pharmacologic management, the mortality rate from septic shock remains high. Care of patients with sepsis includes measures to support the circulatory system and treat the underlying infection. There is a substantial body of knowledge indicating that fluid resuscitation, vasopressors, and antibiotics accomplish these goals. Recent clinical trials have provided new information on the addition of individual adjuvant therapies. Consensus on how current therapies should be prescribed is lacking. We present the reasoning and preferences of a group of intensivists who met to discuss the management of an actual case. The focus is on management, with emphasis on the criteria by which treatment decisions are made. It is clear from the discussion that there are areas where there is agreement and areas where opinions diverge. This presentation is intended to show how experienced intensivists apply clinical science to their practice of critical care medicine.

Anti-Bacterial Agents↗
PubMed2005

Modulation of IGF-binding protein-2 and -3 in hyperoxic injury in developing rat lung.

Retinoids play an important role in lung development and repair. We showed that retinoic acid (RA) inhibits O(2)-induced fibroblast proliferation in rat lung explants. IGF-1, which enhances the proliferation of human fetal lung fibroblasts and stimulates collagen production during lung injury, has an important role in the lung injury/repair process. Interactions of IGF-1 with its receptor are modulated by IGF-binding proteins IGFBPs. We hypothesized that RA alters IGFBP-2 and -3 in hyperoxia-exposed neonatal lung and alters collagen production. Neonatal rat lungs were cultured in room air or 95% O(2) and 5% CO(2) for 3 d with or without RA. IGFBP-2 and -3 were measured both in culture medium and in lung tissue. Type I collagen and procollagen propeptide were analyzed in the lung tissue. Hyperoxia induced an increase in type I collagen that was significantly inhibited in the presence of RA. IGFBP-2 and IGFBP-3 in the lungs were decreased in hyperoxia but significantly increased in hyperoxia plus RA. In the culture medium, IGFBP-2 and -3 were not increased with hyperoxia but significantly increased in the presence of RA plus hyperoxia. There was no increase in IGFBP-3 RNA transcript after RA treatment in either room air or O(2) exposure. In conclusion, RA modulates the secreted IGFBP-2 and -3 during O(2) exposure and inhibits the increase in collagen that occurs during lung injury. We speculate that RA protects against O(2)-induced neonatal lung injury through modulation of the IGFBPs.

Animals↗
PubMed2005

Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury.

Hyperoxic acute lung injury (HALI) is characterized by a cell death response with features of apoptosis and necrosis that is inhibited by IL-11 and other interventions. We hypothesized that Bfl-1/A1, an antiapoptotic Bcl-2 protein, is a critical regulator of HALI and a mediator of IL-11-induced cytoprotection. To test this, we characterized the expression of A1 and the oxygen susceptibility of WT and IL-11 Tg(+) mice with normal and null A1 loci. In WT mice, 100% O(2) caused TUNEL(+) cell death, induction and activation of intrinsic and mitochondrial-death pathways, and alveolar protein leak. Bcl-2 and Bcl-xl were also induced as an apparent protective response. A1 was induced in hyperoxia, and in A1-null mice, the toxic effects of hyperoxia were exaggerated, Bcl-2 and Bcl-xl were not induced, and premature death was seen. In contrast, IL-11 stimulated A1, diminished the toxic effects of hyperoxia, stimulated Bcl-2 and Bcl-xl, and enhanced murine survival in 100% O(2). In A1-null mice, IL-11-induced protection, survival advantage, and Bcl-2 and Bcl-xl induction were significantly decreased. VEGF also conferred protection via an A1-dependent mechanism. In vitro hyperoxia also stimulated A1, and A1 overexpression inhibited oxidant-induced epithelial cell apoptosis and necrosis. A1 is an important regulator of oxidant-induced lung injury, apoptosis, necrosis, and Bcl-2 and Bcl-xl gene expression and a critical mediator of IL-11- and VEGF-induced cytoprotection.

Animals↗
PubMed2003

Interleukin-11 and interleukin-6 protect cultured human endothelial cells from H2O2-induced cell death.

Acute lung injury is a frequent and treatment-limiting consequence of therapy with 100% oxygen. Previous studies have determined that both interleukin (IL)-6 and IL-11 are protective in oxygen toxicity. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals, and both IL-6 and IL-11 markedly diminished this cell death response. However, the mechanism(s) by which these cytokines protect cells from death is unclear. In the present study, we characterized the effects of H2O2 on subconfluent human umbilical vein endothelial cell (HUVEC) and human pulmonary microvascular endothelial cell (HPMEC) cultures. We found that preincubation of HUVEC cultures with either IL-6 or IL-11 diminished H2O2 (1.0 mM)-induced cell death. Similar effects were noted with HPMEC showing that this effect is not HUVEC-specific. The protective effects of both IL-6 and IL-11 were not associated with any changes in antioxidants and were decreased by approximately 80% in the presence of U0126, a specific inhibitor of MEK-1-dependent pathways. The cytoprotective effects of IL-11 and IL-6 were also completely eliminated in STAT3 dominant-negative transduced HUVEC cultures. These studies demonstrate that IL-6 and IL-11 both confer cytoprotective effects that diminish oxidant-mediated endothelial cell injury. They also demonstrate that this protection is mediated, at least in part, by a STAT3 and MEK-1-dependent specific signal transduction pathway(s).

Antioxidants↗
PubMedDate not supplied

Pulmonary hypertension: work in progress.

Pulmonary arterial hypertension is a rare disorder defined by mean pulmonary artery pressures that exceed 25 mm Hg at rest or are greater than 30 mm Hg with exercise. The mortality rate is high for untreated patients, mainly as a result of progressive right heart dysfunction. Pulmonary arterial hypertension has been historically classified as primary pulmonary hypertension or pulmonary hypertension resulting from an underlying disease process. Ongoing research in the nuclear medicine field holds great promise for understanding the pathophysiologic pathways for this condition, as well as the monitoring of the continually evolving therapeutic options.

Blood Pressure↗