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1.
Mo Med ; 118(4): 363-373, 2021.
Article in English | MEDLINE | ID: mdl-34373673

ABSTRACT

PURPOSE OF STUDY: Plastic Bronchitis (PB) is a rare pulmonary condition characterized by the presence of casts in the trachea or bronchial tree. While there are many individual cases reported in pediatric and adult populations, no thorough reviews of pediatric and adult cases of PB exist in the literature. The purpose of this article is to conduct a comprehensive review of PB regarding presentation, diagnosis, pathophysiology, and treatments. ETIOLOGY: In the pediatric population, PB can be attributed to pediatric cardiothoracic surgeries such as Fontan procedures, infections, inflammatory processes, acute chest syndrome, or iatrogenic processes. In the adult population, PB can be idiopathic or due to infections, anatomic variations in lymphatic vessels, surgeries, medications, or other comorbidities. PATHOPHYSIOLOGY: The pathophysiology of PB is still widely unknown; however, associations with inflammatory diseases and cardiac surgery have been proposed. There are two types of cast formations found in plastic bronchitis: Type I casts are associated with inflammatory diseases and Type II casts are associated with surgical procedures. TREATMENT: Historically, PB has been treated by a variety of pharmacological methods including the use of corticosteroids and mucolytics. Recently, the treatment paradigm has shifted towards procedures such as lymphatic embolization, duct ligation, and stent grafting. CONCLUSIONS: The information available regarding PB is still sparse, hence future research is necessary for further understanding of the disease. Due to its numerous presentations and disease associations, awareness of plastic bronchitis, and its treatment options is essential for primary care providers and respiratory specialists.


Subject(s)
Bronchitis , Fontan Procedure , Lymphatic Vessels , Adrenal Cortex Hormones , Adult , Bronchitis/diagnosis , Bronchitis/therapy , Child , Humans , Plastics
2.
Cell Stem Cell ; 21(1): 120-134.e7, 2017 07 06.
Article in English | MEDLINE | ID: mdl-28506464

ABSTRACT

To investigate the role of immune cells in lung regeneration, we used a unilateral pneumonectomy model that promotes the formation of new alveoli in the remaining lobes. Immunofluorescence and single-cell RNA sequencing found CD115+ and CCR2+ monocytes and M2-like macrophages accumulating in the lung during the peak of type 2 alveolar epithelial stem cell (AEC2) proliferation. Genetic loss of function in mice and adoptive transfer studies revealed that bone marrow-derived macrophages (BMDMs) traffic to the lung through a CCL2-CCR2 chemokine axis and are required for optimal lung regeneration, along with Il4ra-expressing leukocytes. Our data suggest that these cells modulate AEC2 proliferation and differentiation. Finally, we provide evidence that group 2 innate lymphoid cells are a source of IL-13, which promotes lung regeneration. Together, our data highlight the potential for immunomodulatory therapies to stimulate alveologenesis in adults.


Subject(s)
Lung/physiology , Macrophages, Alveolar/immunology , Monocytes/immunology , Pneumonectomy , Regeneration/immunology , Th2 Cells/immunology , Animals , Interleukin-13/genetics , Interleukin-13/immunology , Mice , Mice, Knockout , Receptor, Macrophage Colony-Stimulating Factor/genetics , Receptor, Macrophage Colony-Stimulating Factor/immunology , Receptors, CCR2/genetics , Receptors, CCR2/immunology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Regeneration/genetics
4.
BMC Dev Biol ; 15: 32, 2015 Sep 16.
Article in English | MEDLINE | ID: mdl-26376663

ABSTRACT

Recent studies have identified epithelial stem and progenitor cell populations of the lung. We are just beginning to understand the mechanisms that regulate their homeostatic, regenerative and maladaptive behaviors. Here, we discuss evidence of regulatory niches for epithelial stem cells of the lung.


Subject(s)
Airway Remodeling , Lung/cytology , Stem Cell Niche , Animals , Bronchi/cytology , Disease Models, Animal , Fibrosis/pathology , Humans , Lung/pathology , Mice , Pulmonary Alveoli/cytology
5.
Eur J Pharmacol ; 740: 346-52, 2014 Oct 05.
Article in English | MEDLINE | ID: mdl-25041842

ABSTRACT

Previously it was reported that combining antibiotics with L-97-1, an adenosine A1 receptor antagonist, significantly improves survival and blocks acute lung injury induced by Yersinia pestis CO 99 in a rat model of pneumonic plague. In the current studies using a conscious rat model of cecal ligation and puncture (CLP) sepsis, L-97-1 was administered in daily intravenous infusions in combination with antibiotics to simulate the use of L-97-1 as an anti-sepsis therapeutic in the clinical setting. In these studies, when administered at 12 h following CLP, in combination with broad spectrum antibiotics, ceftriaxone and clindamycin, L-97-1 improves 7 day (d) survival [25%, 35%, and 75% for L-97-1 (10 mg/kg/h, 12.5 mg/kg/h, and 15 mg/kg/h, respectively) versus (vs.) 25% for antibiotics alone] in a dose-dependent manner. The addition of L-97-1, 15 mg/kg/h to antibiotics significantly increased 7 d survival following CLP compared to therapy with either antibiotics alone (P=0.002) or L-97-1 at 15 mg/kg/h alone (P<0.001) and was not significantly different than survival in sham CLP animals (Log-rank (Mantel-Cox) test with Bonferroni׳s correction for multiple comparisons). Moreover, in these studies, in combination with antibiotics L-97-1 dose-dependently protects the kidney, significantly improving renal function at 24 h post CLP at 10 mg/kg/h (P<0.001), 12.5 mg/kg/h (P<0.0001), and 15 mg/kg/h (P<0.0001) vs. antibiotics alone (ANOVA followed by Tukey׳s post-hoc test for pair-wise comparisons). The results of these studies support efficacy for L-97-1 as an anti-sepsis therapeutic.


Subject(s)
Adenosine A1 Receptor Antagonists/therapeutic use , Anti-Bacterial Agents/therapeutic use , Kidney/drug effects , Peritonitis/drug therapy , Protective Agents/therapeutic use , Purines/therapeutic use , Sepsis/drug therapy , Adenosine A1 Receptor Antagonists/pharmacology , Animals , Blood Urea Nitrogen , Cecum/surgery , Ceftriaxone/therapeutic use , Clindamycin/therapeutic use , Cytokines/blood , Disease Models, Animal , Drug Therapy, Combination , Ligation , Male , Peritonitis/blood , Protective Agents/pharmacology , Purines/pharmacology , Rats, Sprague-Dawley , Sepsis/blood
6.
Dev Cell ; 22(3): 651-9, 2012 Mar 13.
Article in English | MEDLINE | ID: mdl-22387002

ABSTRACT

The placenta is a hematopoietic organ that supports hematopoietic stem/progenitor cell (HSPC) generation and expansion without promoting differentiation. We identified PDGF-B signaling in trophoblasts as a key component of the unique placental hematopoietic microenvironment that protects HSPCs from premature differentiation. Loss of PDGF-B or its receptor, PDGFRß, induced definitive erythropoiesis in placental labyrinth vasculature. This was evidenced by accumulation of CFU-Es and actively proliferating definitive erythroblasts that clustered around central macrophages, highly reminiscent of erythropoiesis in the fetal liver. Ectopic erythropoiesis was not due to a requirement of PDGF-B signaling in hematopoietic cells but rather in placental trophoblasts, which upregulated Epo in the absence of PDGF-B signaling. Furthermore, overexpression of hEPO specifically in the trophoblasts in vivo was sufficient to convert the placenta into an erythropoietic organ. These data provide genetic evidence of a signaling pathway that is required to restrict erythroid differentiation to specific anatomical niches during development.


Subject(s)
Hematopoietic Stem Cells/physiology , Placenta/physiology , Proto-Oncogene Proteins c-sis/physiology , Signal Transduction/physiology , Trophoblasts/physiology , Animals , Cell Differentiation/physiology , Erythroid Precursor Cells/physiology , Erythropoiesis/physiology , Erythropoietin/physiology , Female , Hematopoietic Stem Cells/cytology , Humans , Macrophages/cytology , Macrophages/physiology , Mice , Placenta/cytology , Pregnancy , Proto-Oncogene Proteins c-sis/genetics , Receptor, Platelet-Derived Growth Factor beta/physiology , Trophoblasts/cytology
7.
Innate Immun ; 18(3): 373-89, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21862597

ABSTRACT

Yersinia pestis, a Gram-negative bacillus causing plague and Centers for Disease Control and Prevention (CDC) classified Category A pathogen, has high potential as a bioweapon. Lipopolysaccharide, a virulence factor for Y. pestis, binds to and activates A(1) adenosine receptor (AR)s and, in animals, A(1)AR antagonists block induced acute lung injury (ALI) and increase survival following cecal ligation and perforation. In this study, rats were infected intratracheally with viable Y. pestis [CO99 (pCD1( + )/Δpgm) 1 × 10( 8 ) CFU/animal] and treated daily for 3 d with ciprofloxacin (cipro), the A(1)AR antagonist L-97-1, or cipro plus L-97-1 starting at 0, 6, 24, 48, or 72 h post-Y. pestis. At 72 h post-Y. pestis, cipro plus L-97-1 significantly improved 6-d survival to 60-70% vs 28% for cipro plus H(2)O and 33% for untreated Y. pestis controls (P = 0.02, logrank test). Lung edema, hemorrhage and leukocyte infiltration index (LII) were evaluated histologically to produce ALI scores. Cipro plus L-97-1 significantly reduced lung edema, as well as aggregate lung injury scores vs controls or cipro plus H(2)O, and LII vs controls (P < 0.05, Student's unpaired t test). These results support efficacy for L-97-1 as a post-exposure medical countermeasure, adjunctive therapy to antibiotics for Y. pestis.


Subject(s)
Acute Lung Injury/prevention & control , Lung/drug effects , Plague/drug therapy , Purines/administration & dosage , Yersinia pestis/immunology , Acute Lung Injury/etiology , Animals , Ciprofloxacin/administration & dosage , Ciprofloxacin/adverse effects , Disease Models, Animal , Drug Therapy, Combination , Humans , Lipopolysaccharides , Lung/immunology , Lung/microbiology , Lung/pathology , Plague/complications , Plague/immunology , Protein Binding/drug effects , Purines/adverse effects , Rats , Receptor, Adenosine A1/metabolism , Virulence Factors , Yersinia pestis/drug effects , Yersinia pestis/pathogenicity
8.
Mo Med ; 107(4): 252-8, 2010.
Article in English | MEDLINE | ID: mdl-20806836

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a spectrum of acute respiratory failure with diffuse, bilateral lung injury and severe hypoxemia caused by non-cardiogenic pulmonary edema. Failure may be initiated by pulmonary or extrapulmonary insults (e.g., pneumonia, sepsis, trauma, aspiration) that increase alveolar epithelial endothelial permeability, flood alveoli, and reduce lung compliance. The only treatment proven to improve survival is mechanical ventilation using a 'lung protective strategy' with tidal volume =6 mL/kg predicted body weight. Although mortality can exceed 50%, survivors have a good prognosis for recovery of lung function.


Subject(s)
Acute Lung Injury/physiopathology , Acute Lung Injury/therapy , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , Humans , Respiration, Artificial , Ventilator-Induced Lung Injury/prevention & control
9.
Respir Physiol Neurobiol ; 172(1-2): 63-71, 2010 Jun 30.
Article in English | MEDLINE | ID: mdl-20470909

ABSTRACT

Reductions in alveolar oxygenation during lung hypoxia/reoxygenation (H/R) injury are common after gram-negative endotoxemia. However, the effects of H/R on endotoxin-stimulated cytokine production by alveolar macrophages are unclear and may depend upon thresholds for hypoxic oxyradical generation in situ. Here TNF-alpha and IL-1beta production were determined in rat alveolar macrophages stimulated with Escherichia coli lipopolysaccharide (LPS, serotype O55:B5) while exposed to either normoxia for up to 24h, to brief normocarbic hypoxia (1.5h at an atmospheric PO(2)=10+/-2mm Hg), or to combined H/R. LPS-induced TNF-alpha and IL-1beta were reduced at the peak of hypoxia and by reoxygenation in LPS+H/R cells (P<0.01) compared with normoxic controls despite no changes in reduced glutathione (GSH) or in PGE2 production. Both TNF-alpha mRNA and NF-kappaB activation were reduced by hypoxia that suppressed superoxide anion generation. Thus, dynamic reductions in the ambient PO(2) of alveolar macrophages that do not deplete GSH suppress LPS-induced TNF-alpha expression, IL-1beta production, and NF-kappaB activation even as oxyradical production is decreased.


Subject(s)
Cell Hypoxia/physiology , Cytokines/metabolism , Lipopolysaccharides/pharmacology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , NF-kappa B/metabolism , Analysis of Variance , Animals , Cell Line, Transformed , Cytokines/genetics , Dinoprostone/metabolism , Electrophoretic Mobility Shift Assay/methods , Gene Expression Regulation/drug effects , Glutathione/metabolism , L-Lactate Dehydrogenase/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Superoxides/metabolism , Time Factors , Transcription Factor AP-1/metabolism
10.
Crit Care Med ; 38(7): 1574-83, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20400901

ABSTRACT

OBJECTIVE: Pneumonic plague resulting from Yersinia pestis induces swiftly lethal sepsis and is a major concern as a weapon of bioterrorism. However, the role of specific plasmid-encoded vs. chromosomal Y. pestis virulence factors in the pathogenesis of acute lung injury, shock, and nonpulmonary dysfunction is unclear. We hypothesized that the pathophysiology of pneumonic plague resulting from expression of proteins encoded by the thermally regulated pCD1 plasmid differs from cardiopulmonary and inflammatory changes attributable to the chromosomal pgm gene locus. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university medical center. SUBJECTS: Conscious, chronically catheterized male Sprague-Dawley rats (total n=104). INTERVENTIONS: Rats were intratracheally infected with 109 colony-forming units of Y. pestis attenuated strains CO99 (pCD1+/DeltaApgm) or KIM6+ (pCD1-/pgm+) and evaluated over 6 days. Serial evaluations of vital signs, cardiorespiratory parameters, blood cultures, inflammatory biomarkers, and organ function were obtained, as well as organ histopathology and cytokine production. MEASUREMENTS AND MAIN RESULTS: Despite equivalent endotoxin contents between the inocula, CO99-infected animals had a median survival of 3 days with greater nonpulmonary organ injury, microbial growth, serum alanine aminotransferase, and liver microvascular permeability vs. KIM6+-infected animals (p<.05). Parallel differences occurred in serum tumor necrosis factor-alpha levels. Notably, 75% of CO99 rats developed fatal hypotension after developing nonpulmonary organ damage. CONCLUSION: These results suggest that progression to lethal sepsis with augmented liver injury during plague pneumonia requires factors encoded by the pCD1 plasmid but not chromosomal proteins present within the pgm gene locus.


Subject(s)
Bacterial Proteins/physiology , Multiple Organ Failure/physiopathology , Plague/physiopathology , Shock, Septic/physiopathology , Virulence Factors/physiology , Yersinia pestis/physiology , Alanine Transaminase/blood , Animals , Bacterial Proteins/genetics , Capillary Permeability , Cytokines/blood , Enzyme-Linked Immunosorbent Assay , Genes, Bacterial , Genetic Loci , Hemodynamics , Liver/blood supply , Male , Multiple Organ Failure/etiology , Multiple Organ Failure/microbiology , Plague/complications , Plague/microbiology , Plasmids , Rats , Rats, Sprague-Dawley , Shock, Septic/etiology , Shock, Septic/microbiology , Virulence Factors/genetics , Yersinia pestis/genetics
11.
J Neuroimmunol ; 181(1-2): 82-92, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17045344

ABSTRACT

CB(2) cannabinoid receptors exist in immune cells including macrophages. Affinity-purified antibodies against the CB(2) receptor identified a 45 kDa protein in rat brain, human tonsil and rat and mouse microglia, but not mouse N18TG2 neuroblastoma cells. Intracerebroventricular lipopolysaccharide (LPS) increased immunoreactive CB(2) receptors in brain membranes detected by Western blot. LPS increased immunodetectable CB(2) receptors in cultured RAW 264.7 macrophages, and this was partially attenuated by cyclohexamide or the protein kinase A and C inhibitors H8 and bis-indolylmaleimide. Forskolin or dibutyryl cyclic AMP increased CB(2) receptor immunoreactivity, suggesting the involvement of the cyclic AMP-protein kinase A-Cyclic AMP response element pathway in the regulation of CB(2) receptor levels.


Subject(s)
Cyclic AMP/metabolism , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Receptor, Cannabinoid, CB2/metabolism , Animals , Cell Line , Cyclic AMP-Dependent Protein Kinases/metabolism , Cycloheximide/pharmacology , Macrophages/cytology , Membrane Proteins/metabolism , Mice , Microglia/cytology , Microglia/drug effects , Microglia/metabolism , Prosencephalon/cytology , Protein Synthesis Inhibitors/pharmacology , Rats , Up-Regulation/drug effects
12.
Adv Physiol Educ ; 29(2): 118-27, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15905157

ABSTRACT

We describe an animal laboratory using anesthetized swine to demonstrate the regulation of arterial blood pressure to second-year medical students at Saint Louis University School of Medicine (St. Louis, MO). The laboratory is designed to illustrate basic pharmacological and physiological concepts learned in the classroom. The specific learning objectives covered in this lab include maintenance of anesthesia, basic surgical technique including cannulation of blood vessels, understanding the measurement and significance of basic physiological parameters, premortem examination of in situ heart and lungs, direct cardiac massage and induction of ventricular fibrillation, understanding the fundamentals of the baroreceptor reflex, and cardiovascular responses to various pharmacological agents. Pharmacologic agents used include epinephrine, norepinephrine, isoproterenol, atropine, prazosin, propranolol, acetylcholine, nitroprusside, and angiotensin II. The laboratory demonstration has proven effective in reinforcing the fundamental principles of cardiovascular physiology and autonomic pharmacology. By the completion of this experiment, students are expected to be able to: 1) describe the basics of maintenance of anesthesia in a live animal; 2) describe basic surgical technique; 3) observe the procedure for proper cannulation of blood vessels; 4) describe the proper method of controlling hemorrhage from a bleeding source; 5) describe the measurement and recording of four physiological parameters: mean arterial pressure from a pressure transducer, heart rate from an ECG, hindquarters resistance from Doppler measurement of femoral arterial blood flow, and cardiac contractility by calculating dP/dt from left ventricular pressure measured with a Millar transducer; 6) perform a premortem exam of the heart and lungs and appreciate the in situ cardiothoracic anatomy of the living animal; 7) assist in the induction of ventricular fibrillation and perform direct cardiac massage; 8) characterize the autonomic responses activated by the baroreceptor reflex; 9) describe the effects of the adrenergic agonists epinephrine, norepinephrine, and isoproterenol on cardiovascular parameters and construct a dose response curve for each agent; 10) describe the effects of the adrenergic antagonists propranolol and prazosin on cardiovascular parameters and explain how they affect cardiovascular responses to adrenergic agonists; 11) describe the difference between endothelium-dependent and endothelium-independent vasodilation using acetylcholine, nitroprusside, and atropine; 12) observe the pressor response of angiotensin II and describe why this response is not blocked by pretreatment with prazosin; and 13) participate in the collection and analysis of experimental data and the presentation of results.


Subject(s)
Cardiovascular Physiological Phenomena , Laboratories , Students, Medical , Teaching/methods , Animals , Cardiovascular Physiological Phenomena/drug effects , Dose-Response Relationship, Drug , Epinephrine/pharmacology , Humans , Schools, Medical , Swine
13.
Am J Physiol Regul Integr Comp Physiol ; 287(2): R437-45, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15059791

ABSTRACT

Transactivation of the DNA-binding proteins nuclear factor-kappa B (NF-kappa B) and activator protein (AP)-1 by de novo oxyradical generation is a stereotypic redox-sensitive process during hypoxic stress of the liver. Systemic trauma is associated with splanchnic hypoxia-reoxygenation (H/R) followed by intraportal gram-negative bacteremia, which collectively have been implicated in posttraumatic liver dysfunction and multiple organ damage. We hypothesized that hypoxic stress of the liver before stimulation by Escherichia coli serotype O55:B5 (EC) amplifies oxyradical-mediated transactivation of NF-kappa B and AP-1 as well as cytokine production compared with noninfectious H/R or gram-negative sepsis without prior hypoxia. Livers from Sprague-Dawley rats underwent perfusion for 180 min with or without 0.5 h of hypoxia (perfusate PO(2), 40 +/- 5 mmHg) followed by reoxygenation and infection with 10(9) EC or 0.9% NaCl infusion. In H/R + EC livers, nuclear translocation of NF-kappa B and AP-1 was unexpectedly reduced in gel shift assays vs. normoxic EC controls, as were perfusate TNF-alpha and IL-1 beta levels. Preceding hypoxic stress paradoxically increased postbacteremic reduced-to-oxidized glutathione ratios plus nuclear localization of I kappa B alpha and phospho-I kappa B alpha, but not JunB/FosB profiles. Notably, xanthine oxidase inhibition increased transactivation as well as cytokine production in H/R + EC livers. Thus brief hypoxic stress of the liver before intraportal gram-negative bacteremia potently suppresses activation of canonical redox-sensitive transcription factors and production of inflammatory cytokines by mechanisms including xanthine oxidase-induced oxyradicals functioning in an anti-inflammatory signaling role. These results suggest a novel multifunctionality of oxyradicals in decoupling hepatic transcriptional activity and cytokine biosynthesis early in the posttraumatic milieu.


Subject(s)
Escherichia coli Infections/metabolism , Hypoxia/metabolism , NF-kappa B/metabolism , Signal Transduction/physiology , Transcription Factor AP-1/metabolism , Animals , Cell Nucleus/metabolism , Cytokines/metabolism , Cytoplasm/metabolism , Escherichia coli Infections/physiopathology , Glutathione/metabolism , Glutathione Disulfide/metabolism , Hypoxia/physiopathology , I-kappa B Proteins/metabolism , Liver/metabolism , Male , NF-KappaB Inhibitor alpha , NF-kappa B/genetics , Oxidation-Reduction , Oxidative Stress/physiology , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Transcription Factor AP-1/genetics , Transcription, Genetic/physiology , Xanthine Oxidase/antagonists & inhibitors
14.
Crit Care Med ; 32(1): 175-83, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14707577

ABSTRACT

OBJECTIVE: We hypothesized that the sympathomimetic cocaine may alter cardiovascular and inflammatory responses and enhance susceptibility to endotoxemia due to innate differences in patterns of sympathetic and cardiovascular responsiveness. DESIGN: Prospective study. SETTING: Experimental animal laboratory. SUBJECTS: Fifty-six conscious, instrumented albino rats. INTERVENTIONS: Rats were instrumented for determination of arterial pressure and intravenous drug administration and, in some rats, for cardiac output. After recovery, rats were given cocaine (5 mg/kg i.v., twice daily with 4-6 trials) to identify one of two hemodynamic response patterns: a) an increase in systemic vascular resistance with cardiac depression (vascular responders) or b) smaller increases in systemic vascular resistance and no change or an increase in cardiac output (mixed responders). At least 1 month after characterizing response patterns to cocaine, animals were pretreated with cocaine (5 mg/kg i.v.) or an equivalent bolus of vehicle (0.9% saline) while recording hemodynamics. Five minutes later, Escherichia coli lipopolysaccharide (serotype O55:B5, 20 mg/kg i.v.) was administered for 15 mins. MEASUREMENTS AND MAIN RESULTS: Hemodynamic responses, pupillary diameter, and serum cytokines were determined at several time points. Lipopolysaccharide administration (5-40 mg/kg) without cocaine produced dose-dependent depressor responses with recovery typically within 2 hrs. Although 87% of rats survived a single 20 mg/kg dose of lipopolysaccharide when given alone, pretreatment of vascular responders with cocaine before lipopolysaccharide resulted in greater increases in systemic vascular resistance and pupillary mydriasis and lethality in five of six vascular responders, whereas only one of six mixed responders died. Pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.1 mg/kg i.v.) before cocaine and lipopolysaccharide attenuated hemodynamic responses and improved survival among vascular responders. Serum interleukin-6 and interleukin-10 were elevated in rats treated with cocaine and lipopolysaccharide compared with rats treated with lipopolysaccharide alone, whereas serum tumor necrosis factor-alpha was reduced by cocaine pretreatment. Moreover, serum interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 were elevated in nonsurvivors compared with survivors after cocaine and lipopolysaccharide administration. CONCLUSIONS: We conclude that cocaine enhances susceptibility and worsens outcome from endotoxic shock by augmenting sympathetic activity, particularly in vascular responders, and that alpha-adrenoceptors mediate the altered inflammatory responses.


Subject(s)
Cocaine/adverse effects , Disease Susceptibility , Endotoxemia/physiopathology , Hemodynamics/drug effects , Shock, Septic/physiopathology , Animals , Blood Pressure/drug effects , Cardiac Output/drug effects , Cardiac Output/physiology , Cocaine/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Injections, Intravenous , Male , Rats , Rats, Inbred Strains , Reference Values , Sensitivity and Specificity , Vascular Resistance/drug effects , Vascular Resistance/physiology
15.
Crit Care Med ; 31(1): 237-45, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12545022

ABSTRACT

OBJECTIVES: We have shown previously that inactivation of catecholamines by superoxide anions contributes to the loss of vascular reactivity to norepinephrine and the subsequent hypotension that develops in Gram-negative endotoxic shock. In addition to their vasopressor actions, catecholamines, via beta-adrenoceptor activation, are important regulators of cytokine production. Here we examined if maintenance of serum catecholamine levels by the superoxide dismutase mimetic, M40401, modulates serum cytokine levels and arterial hypotension in an Escherichia coli-infected conscious rat model of septic shock. DESIGN: Controlled laboratory animal study. SETTING: University animal research laboratory. SUBJECTS: Pathogen-free male Sprague-Dawley rats (n = 51). INTERVENTIONS: Conscious, antibiotic-treated animals with chronic in-dwelling carotid arterial and jugular venous catheters were intravenously infected with 10(10) live E. coli bacteria (O55:B5, n = 51) over 30 mins, ending at time = 0 hrs. At 0.5 or 3 hrs, infected rats were administered an intravenous infusion of either M40401 (n = 33) or 0.9% saline (n = 18) for 6 hrs at a rate of 1 mL/h. In additional experiments, anesthetized animals with catheterized left femoral arteries and veins were administered a dose-range of norepinephrine (0.1-1 microg/kg) as bolus intravenous injections. Thereafter, E. coli lipopolysaccharide (4 mg/kg, n = 6) was administered as a 0.3-mL slow bolus intravenous injection. One hour later, the norepinephrine protocol was repeated, after which the rats were administered an intravenous infusion of either M40401 or 0.9% saline for 15 mins. At 2 hrs, the dose response to norepinephrine was repeated. MEASUREMENTS AND MAIN RESULTS: Rats infected with live E. coli exhibited a biphasic fall in mean arterial pressure, with mortality reaching 83% by 24 hrs. Rats treated with M40401 (0.25, 2.5, or 25 microg x kg-1 x hr-1 ) 3 hrs after bacteremic sepsis maintained a normal mean arterial pressure, and mortality was dose-dependently reduced to 44, 33, and 22%, respectively, at 24 hrs. Furthermore, serum catecholamine levels were diminished in E. coli-infected rats treated with saline compared with rats treated with M40401. In separate experiments, E. coli-infected rats were administered M40401 (25 microg x kg-1 x hr-1 ) 0.5 hr after bacterial challenge. Blood samples taken at 0, 1.5, 3.5, and 6 hrs were analyzed for tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, and IL-10 and for norepinephrine and epinephrine. Serum levels of tumor necrosis factor-alpha and IL-1 beta were significantly depressed in M40401-treated septic rats, whereas IL-10 was elevated. Moreover, serum catecholamine levels were greater in M40401-treated septic rats at the same time points. IL-6 levels were unaffected by M40401 treatment. Finally we examined whether treatment with M40401 could reverse the hyporeactivity to norepinephrine typifying early septic shock. Using the E. coli lipopolysaccharide (4 mg/kg) challenged anesthetized rat model of shock, we demonstrated that the vasoconstrictor ability of norepinephrine was indeed restored after M40401 treatment (25 microg/kg). CONCLUSION: Postinfection treatment with the superoxide dismutase mimetic M40401 protects against hypotension, vascular hyporeactivity to catecholamines, and mortality associated with septic shock. Such beneficial effects correlate with both reduced oxidative inactivation of serum catecholamines and a reduction in canonical cytokine mediators of inflammation.


Subject(s)
Catecholamines/blood , Cytokines/drug effects , Free Radical Scavengers/pharmacology , Organometallic Compounds/pharmacology , Shock, Septic/drug therapy , Superoxide Dismutase/pharmacology , Analysis of Variance , Animals , Cytokines/blood , Free Radical Scavengers/therapeutic use , Hypotension/prevention & control , Male , Organometallic Compounds/therapeutic use , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Shock, Septic/immunology , Superoxide Dismutase/therapeutic use , Survival Analysis
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