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D R Meldrum

Publications and source records attributed to D R Meldrum.

At least 55 records · Page 3Linked to original sources
PubMed1998

Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production. Potential ultimate effector mechanism of preconditioning.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion (I/R) injury, sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leukocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether ischemic preconditioning, which is mediated by adenosine, decreases postischemic myocardial TNF-alpha production. METHODS AND RESULTS: Isolated rat hearts were crystalloid perfused with the Langendorff method and subjected to global, normothermic I/R (20/40 minutes), with or without prior transient ischemic preconditioning (5 minutes) or adenosine pretreatment. Postischemic cardiac TNF-alpha (ELISA) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Ischemic preconditioning or adenosine decreased myocardial TNF-alpha and improved postischemic functional recovery. Sequestration of myocardial TNF-alpha (TNF binding protein) during the I/R experiments similarly improved postischemic myocardial function. CONCLUSIONS: This study constitutes the initial demonstration that in addition to its other beneficial effects, preconditioning decreases postischemic myocardial TNF-alpha, an autocrine contributor to postischemic myocardial dysfunction. Reduced myocardial TNF-alpha production may represent the distal effector mechanism of preconditioning.

Animals↗
PubMed1998

Capillary tube resistive thermal cycling.

A system that performs rapid thermal cycling of microliter and smaller liquid volumes inside glass capillary tubes that have an optically transparent thin film of indium-tin oxide (ITO) covering the exterior is described. The ITO film acts as both a heater and a temperature sensor, while cooling is accelerated with forced air. Unlike existing batch-mode thermal cycling systems, this system allows control over each sample's temperature profile. Temperature transition rates of 44 degrees Celsius per second during heating and 15 degrees Celsius per second during cooling have been achieved, allowing successful polymerase chain reaction (PCR) experiments to be performed in 20 min. Capillary external temperature can be regulated typically to within +/- 0.25 degrees Celsius, and peak temperatures more than 800 degrees Celsius have been demonstrated. Capillary internal (sample) temperatures at present are controllable typically to within 2 degrees Celsius. The resistive film can be used as a temperature sensor, and the optical transparency of the thin-film coating could permit fluorescent monitoring of the sample during thermal cycling, making this method well suited for real-time quantitative PCRs.

Microchemistry↗
PubMed1998

Genes don't count.

It is the regulation of gene expression that determines phenotype and cellular response. Several families of proteins control gene expression in cells and influence the pathogenesis of multiple organ failure, the acute phase response, atherosclerosis, and graft-vs-host disease. Understanding the basics of the regulation of gene transcription will allow the knowledgeable surgeon to target gene expression as a therapeutic modality in multiple diseases. We examine nuclear factor kappa B as an example of a transcription factor that is involved in multiple surgical diseases and has pharmacological inhibitors available to knowledgeable surgeons.

Animals↗
PubMed1998

Human myocardial tissue TNFalpha expression following acute global ischemia in vivo.

Although human myocardial TNFalpha levels are increased during the ischemia associated with chonic heart failure, it remains unknown whether an acute global ischemic insult further increases TNFalpha expression in human cardiac myocytes. To study this, biopsies of human myocardium were obtained before and after cardiopulmonary bypass (in vivo acute global ischemia), and myocardial TNFalpha levels were determined by ELISA and cytotoxicity assay (WEHI-164 clone 13 cell line). TNFalpha was immunolocalized by immunohistochemistry. Results indicate that cardiopulmonary bypass induces an increase in human myocardial TNFalpha by both ELISA and cytotoxicity assays. Immunolocalization revealed that prior to cardiopulmonary bypass TNFalpha was located predominantly in the myocardial interstitial cells; however, following bypass, increased TNFalpha was observed in the cardiocytes themselves. Locally-produced myocardial TNFalpha may be an important contributor to myocardial functional depression and injury following acute ischemia. Targeted anti-TNFalpha therapy in the treatment of cardiac ischemic injury may further elucidate its clinical relevance.

Biopsy↗
PubMed1998

Adenosine reduces cardiac TNF-alpha production and human myocardial injury following ischemia-reperfusion.

Myocardial tumor necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury (I/R), sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages and cardiomyocytes themselves produce TNF-alpha. In this regard, adenosine (ADO) has been reported to reduce macrophage TNF-alpha production. Our purposes were to determine whether (1) I/R induces rat myocardial TNF-alpha production; (2) ADO decreases ischemia-induced rat myocardial TNF-alpha production; (3) ADO functionally protects human myocardium against I/R; and (4) TNF-alpha-binding protein (TNFBP; p55) confers similar protection when substituted for ADO pretreatment. To study this, human atrial trabeculae were obtained during cardiac surgery and suspended in organ baths, paced at 1 Hz, and force development was recorded during I/R (45/120 min) with or without ADO pretreatment (125 microM x 10 min), or TNFBP (1 microgram/ml) during I/R. Isolated rat hearts were perfused using the Langendorff method undergoing I/R (20/40 min) with or without ADO pretreatment (125 microM x 2 min) and rat myocardial expression of TNF-alpha was assessed by ELISA. Results demonstrated that I/R increased rat myocardial TNF-alpha levels from 324 +/- 36 to 902 +/- 77 pg/g (P < 0.05; ANOVA and Bonferroni/Dunn) and decreased human myocardial developed force (DF) to 18 +/- 2% of baseline (%BDF; P < 0.05). ADO pretreatment decreased ischemia-induced rat myocardial TNF-alpha production (356 +/- 107 pg/g; P < 0.05) and increased postischemic DF of human myocardium to 39 +/- 3% BDF (P < 0.05. Further substantiating the link between ischemia-induced TNF-alpha production and injury, TNFBP administration similarly improved post-I/R function of human myocardium (55 +/- 5% BDF; P < 0.05 vs. I/R alone). We conclude that (1) I/R induces rat myocardial TNF-alpha production; (2) ADO pretreatment decreases I/R-induced rat myocardial TNF-alpha production; (3) ADO improves human myocardial function; (4) TNFBP confers similar protection; and (5) inhibition/neutralization of TNF-alpha represents a novel strategy for protecting human myocardium against ischemia and reperfusion injury.

Adenosine↗
PubMed1998

Therapeutic antidysrhythmic and functional protection in human atria.

Approximately 30% of patients suffer supraventricular dysrhythmias after cardiac bypass. While the heart can be constructively preconditioned to maintain function against subsequent ischemic insult using a variety of stimuli across many species, preconditioning in experimental animals is associated with decreased postischemic reperfusion cardiac dysrhythmias. This mode of therapeutic preconditioning has not been previously examined in human atrial myocardium. We therefore hypothesized that preconditioning provides both antidysrhythmic and functional protection to human atria. To study this, human atrial trabeculae were suspended in organ baths, paced at 1 Hz, while force development and ectopy were recorded before and after simulated ischemia. The study consisted of five groups: (1) control trabeculae (n = 12), (2) trabeculae exposed to dysrhythmogenic stimuli (phenylephrine 50 microM and isoproterenol 25 microM (n = 8)), (3) trabeculae exposed to ischemia-reperfusion (I/R) injury and then drug stimulated (n = 10), (4) trabeculae preconditioned with adenosine (ADO 125 microM) then drug stimulated (n = 10), and (5) trabeculae preconditioned with ischemic preconditioning (IPC) then drug stimulated (n = 6) each at end reoxygenation. Differences between groups were assessed using X2 analysis and ANOVA (Bonferroni/Dunn). Results demonstrated that human atrial trabeculae did not exhibit dysrhythmia at baseline or when stimulated with alpha and beta agonists. After I/R, control trabeculae exhibited stimulated reperfusion dysrhythmia, while trabeculae preconditioned with either ADO or transient ischemia exhibited decreased stimulated dysrhythmia (each P < 0.05 vs. I/R). Functionally, I/R decreased developed force (DF) to 16 +/- 2% of baseline (%BDF) while ADO pretreatment increased postischemic DF to 41 +/- 3% BDF (P < 0.05 vs. I/R) while IPC increased DF to 49 +/- 3% BDF (P < 0.05 vs. I/R). We conclude that (1) human atrial trabeculae can ve functionally preconditioned with either ADO or IPC, and (2) protective preconditioning/ cardioprotection does extend to dysrhythmia control and is therapeutically accessible in human atrial myocardium.

Adenosine↗
PubMed1998

Interleukin-10 inhibits postinjury tumor necrosis factor-mediated human vascular smooth muscle proliferation.

BACKGROUND: Both ischemic and direct vascular injury (angioplasty) result in the elaboration of proinflammatory substances, including tumor necrosis factor alpha (TNF), which may regulate vascular smooth muscle cell (VSMC) proliferation and promote vessel stenosis. Interleukin-10 (IL-10) is a pleiotropic cytokine with potent antiinflammatory effects in many cells lines. We hypothesized that IL-10 could be used therapeutically to influence vascular remodeling by inhibiting TNF-induced VSMC proliferation. The purposes of this study were (1) to determine whether human myocardium produces endogenous TNF in response to ischemia-reperfusion, (2) to examine the effect of TNF on human arterial smooth muscle proliferation, and (3) to explore the potential therapeutic effect of IL-10 on unstimulated and TNF-stimulated VSMC proliferation. MATERIALS AND METHODS: Right atrial muscle was obtained from patients undergoing elective cardiac surgery. Atrial muscle was subjected to simulated ischemia and reperfusion in vitro and TNF was measured by immunoassay. Human aortic VSMCs were isolated and cultured. Proliferation assays were performed to determine the effect of TNF and IL-10 on VSMC growth. RESULTS: Ischemia-reperfusion resulted in an increase in atrial myocellular TNF (94.5 +/- 15.8 pg/g wet tissue versus control 12.9 +/- 4.4 pg/g wet tissue, P < 0.002). Compared with control, TNF stimulated concentration-dependent VSMC proliferation (P < 0.005). IL-10 alone did not influence VSMC growth. However, following TNF stimulation, IL-10 inhibited VSMC growth at a dose as low as 0.1 pg/ml (P < 0.005). CONCLUSIONS: Ischemia-reperfusion insult results in increased endogenous myocardial TNF accumulation. TNF stimulates VSMC growth which is abrogated by physiologically relevant levels of IL-10. This antiinflammatory cytokine may prove to be an effective therapeutic agent in regulating vessel wall remodeling following both ischemic and direct cardiovascular injury.

Angioplasty↗
PubMed1998

Assisted hatching reduces the age-related decline in IVF outcome in women younger than age 43 without increasing miscarriage or monozygotic twinning.

PURPOSE: Our purpose was to examine the benefits of assisted hatching in our program and to determine whether the procedure increases the implantation of nonviable embryos or monozygotic twinning. METHODS: Consecutive in vitro fertilization cycles using assisted hatching were compared with historical controls. The impact of assisted hatching was analyzed according to the woman's age. Outcome measures were clinical pregnancy, implantation rate, delivery rate, multiple pregnancy, spontaneous abortion, and incidence of monozygotic twins. RESULTS: The implantation rate was increased in women aged 35-39 and markedly increased in women aged 40-42. There was no change in spontaneous abortions and no increase in monozygotic twins. CONCLUSIONS: Assisted hatching is a safe and highly effective adjunct to in vitro fertilization for women aged 35-42 and did not increase spontaneous abortion or monozygotic twinning.

Abortion, Spontaneous↗
PubMed1998

Increased myocardial tumor necrosis factor-alpha in a crystalloid-perfused model of cardiac ischemia-reperfusion injury.

BACKGROUND: The heart is a tumor necrosis factor-alpha (TNF-alpha)-producing organ. Recent basic experimental and clinical evidence suggests that TNF-alpha is an important mediator of myocardial injury during acute myocardial infarction, chronic heart failure, cardiac allograft rejection, and cardiopulmonary bypass operations. Although it is known that the myocardium itself is capable of producing TNF-alpha in response to endotoxin, it is unknown whether there is an increase in myocardial tissue TNF-alpha levels after ischemia-reperfusion injury. We hypothesized that ischemia-reperfusion induces the production of TNF-alpha by the heart. METHODS: To avoid blood-borne TNF-alpha as a potentially confounding variable, we examined myocardial TNF-alpha production in a crystalloid-perfused model of cardiac ischemia-reperfusion injury. Isolated rat hearts were perfused with crystalloid solution and subjected to ischemia-reperfusion. Postischemic myocardial TNF-alpha was measured using an enzyme-linked immunosorbent assay and correlated with developed pressure, coronary flow, end-diastolic pressure, and creatine kinase loss (assay of activity in coronary effluent). RESULTS: Ischemia-reperfusion induced a marked increase in myocardial TNF-alpha that was associated with decreased myocardial contractility and coronary flow and with increased end-diastolic pressure and postischemic creatine kinase loss. CONCLUSIONS: The heart produces TNF-alpha in response to ischemia-reperfusion. Ischemia-induced TNF-alpha production may contribute to postischemic myocardial stunning, necrosis, or both. Strategies designed to limit ischemia-induced myocardial TNF-alpha production may have therapeutic utility in the settings of planned myocardial ischemic events.

Animals↗
PubMed1998

Calcium preconditioning in human myocardium.

BACKGROUND: Ischemic stress and other protein kinase C (PKC)-linked receptor stimuli can induce rapid cardiac protection against ischemia-reperfusion injury. We and others have demonstrated that exogenous calcium (Ca2+) pretreatment confers PKC-mediated cardiac functional and infarct protection in animal models, but it remains unknown whether Ca2+ preconditioning confers similar postischemic functional protection in human myocardium, and, if so, whether the mechanism is mediated by PKC. We postulated that Ca2+ preconditioning confers ischemic tolerance to human myocardium by a PKC-dependent mechanism. METHODS: Human atrial trabeculae were suspended in organ baths and paced at 1 Hz, and force development was recorded. After 90 minutes of equilibration, all trabeculae were subjected to ischemia (45 minutes) and reperfusion (120 minutes). Exogenous CaCl2 (3.0 mmol/L for 5 minutes) or vehicle (saline solution) was administered before simulated ischemia, with or without concurrent PKC inhibition (bisindolylmaleimide I, 150 nmol/L). RESULTS: Ischemia-reperfusion resulted in decreased postischemic developed force, Ca2+ preconditioning protected human myocardium against ischemia-reperfusion injury (p < 0.05 versus control ischemia-reperfusion), and concurrent PKC inhibition abolished the salutary effect of Ca2+ preconditioning in human myocardium (p < 0.05 versus Ca2+ preconditioning). CONCLUSIONS: Preconditioning with Ca2+ represents a potent means of accessing PKC-mediated protection of the human myocardium against ischemia-reperfusion injury.

Animals↗
PubMed1998

Nitric oxide downregulates lung macrophage inflammatory cytokine production.

BACKGROUND: Inflammatory cytokine production contributes to lung injury after lung ischemia reperfusion and during lung transplant rejection. Although nitric oxide has been demonstrated to reduce lung injury associated with the adult respiratory distress syndrome, it remains unknown whether the mechanism of nitric oxide's beneficial effects involves reducing lung macrophage inflammatory cytokine production. The purpose of this study was to determine whether nitric oxide downregulates lung macrophage inflammatory cytokine production. METHODS: Lung macrophages were harvested by bronchoalveolar lavage (10(6) macrophage per milliliter from normal Sprague-Dawley rats, 6 animals per group) and treated under ex vivo tissue culture conditions with the nitric oxide releasing compound S-nitoso-N-acetyl-D, L-penicillamine (0, 10(-5) 10(-4), 10(-3), 10(-2) mol/L) before induction of inflammatory cytokines with endotoxin, (50 ng/mL for 24 hours). Supernatants were assayed for inflammatory cytokine production (tumor necrosis factor alpha, interleukin-1beta) by enzyme-linked immunosorbent assay. RESULTS: Continuous nitric oxide release by S-nitoso-N-acetyl-D, L-penicillamine decreased lung macrophage tumor necrosis factor-alpha and interleukin-1beta production in a dose-dependent fashion (6 rats per group; data were analyzed for significance [p < 0.05] using two-way analysis of variance with Tukey's post-hoc correction). CONCLUSIONS: Nitric oxide decreases inflammatory cytokine production by lung macrophage. The mechanism of nitric oxide's beneficial effects may be partially attributable to decreased production of inflammatory cytokines. Nitric oxide may serve an expanded role for reducing inflammatory cytokine production during acute lung injury, ischemia-reperfusion-induced inflammation, or lung transplant rejection.

Animals↗
PubMed1998

Success rate with repeated cycles of in vitro fertilization-embryo transfer.

OBJECTIVE: To analyze data from a large multicenter study to determine whether pregnancy and delivery rates decrease with repeated IVF-ET cycles. DESIGN: Multicenter retrospective study. SETTING: Participating centers from the Society of Assisted Reproductive Technology. PATIENT(S): Fifty-four centers contributed 4,043 cycles of oocyte retrieval for uterine transfer. INTERVENTION(S): Oocyte retrieval for uterine transfer. MAIN OUTCOME MEASURE(S): Pregnancy and delivery rates, analyzed according to age, program success rate, and whether the program was doing assisted hatching. RESULT(S): Pregnancy and delivery rates for cycles 1, 2, 3, 4, and >4 were 33.7% and 27.0%, 33.9% and 27.4%, 28.9% and 23.4%. 25.9% and 16.1%, and 21.0% and 15.4%, respectively. The pregnancy rate decreased significantly for >4 cycle; delivery rate decreased significantly for cycles 4 and >4. Assisted hatching was strongly related to better odds of pregnancy (OR, 1.50) and delivery (OR, 1.44) in women under age 40, and for pregnancy (1.64) in women age 40-42 years. CONCLUSION(S): Success rates do not decrease markedly with repeated IVF attempts, and the decrease did not change with program success rate, suggesting the IVF population is not markedly heterogeneous. Uncontrolled studies of new treatments for cycle repeaters cannot assume that success rate is poor without a treatment change.

Adult↗
PubMed1998

Human SERCA2a levels correlate inversely with age in senescent human myocardium.

OBJECTIVES: This study sought to characterize functional impairment after simulated ischemia-reperfusion (I/R) or Ca2+ bolus in senescent human myocardium and to determine if age-related alterations in myocardial concentrations of SERCA2a, phospholamban, or calsequestrin participate in senescent myocardial dysfunction. BACKGROUND: Candidates for elective cardiac interventions are aging, and an association between age and impairment of relaxation has been reported in experimental animals. Function of the sarcoplasmic reticulum resulting in diastolic dysfunction could be dysregulated at the level of cytosolic Ca2+ uptake by SERCA2a, its inhibitory subunit (phospholamban), or at the level of Ca2+ binding by calsequestrin. METHODS: Human atrial trabeculae from 17 patients (45-75 years old) were suspended in organ baths, field simulated at 1 Hz, and force development was recorded during I/R (45/120 min). Trabeculae from an additional 12 patients (53-73 years old) were exposed to Ca2+ bolus (2-3 mmol/L bath concentration). Maximum +/- dF/dt and the time constant of force decay (tau) were measured before and after I/R or Ca2+ bolus and related to age. SERCA2a, phospholamban, and calsequestrin from 12 patients (39-77 years old) were assessed by immunoblot. RESULTS: Functional results indicated that maximum +/-dF/dt and tau were prolonged in senescent (>60 years) human myocardium after I/R (p < 0.05). Calcium bolus increased the maximum +/-dF/dt and decreased tau in younger, but not older patients (p < 0.05). SERCA2a and the ratio of SERCA2a to either phospholamban or calsequestrin were decreased in senescent human myocardium (p < 0.05). CONCLUSIONS: Senescent human myocardium exhibits decreased myocardial SERCA2a content with age, which may, in part, explain impaired myocardial function after either I/R or Ca2+ exposure.

Adult↗
PubMed1998

Hydrogen peroxide induces tumor necrosis factor alpha-mediated cardiac injury by a P38 mitogen-activated protein kinase-dependent mechanism.

BACKGROUND: Oxidant stress caused by ischemia or endotoxemia induces myocardial dysfunction and cardiomyocyte death; however, mechanisms responsible remain unknown. We hypothesized that hydrogen peroxide (H2O2) induces myocardial dysfunction and cardiomyocyte death via P38 mitogen-activated protein kinase (MAPK)-mediated myocardial tumor necrosis factor (TNF) production. METHODS: Langendorff perfused rat hearts (6/group) were subjected to oxidant stress (H2O2 infusion; 300 mmol/L x 80 minutes), with and without prior infusion of a specific P38 kinase MAPK inhibitor (P38i = 1 mmol/L/min x 5 minutes) or TNF neutralization (20 mg TNF binding protein (BP)/min x 80 minutes). Developed pressure (DP), coronary flow, and end-diastolic pressure were continuously recorded. Myocardial creatine kinase (CK) loss was measured in the coronary effluent, and tissue TNF was measured in myocardial homogenates. RESULTS: Eighty minutes of H2O2 infusion induced a 6.5-fold increase in myocardial TNF production, which was associated with a 70% decrease in DP and increase in CK loss. P38 MAPK inhibition or TNF-BP decreased myocardial TNF production, cardiomyocyte death, and myocardial dysfunction. CONCLUSIONS: These results demonstrate that H2O2 alone induces myocardial TNF production. P38 MPAK is an oxidant-sensitive enzyme that mediates oxidant-induced myocardial TNF production, cardiac dysfunction, and cardiomyocyte death.

Animals↗
PubMed1998

Endotoxin differentially impairs receptor-mediated relaxation in rat isolated pulmonary and thoracic aortic vessels.

PURPOSE: The purpose of this study was to determine the effect of endotoxin on vasorelaxation in the pulmonary and systemic circulations in response to the following agonists that require generation of cyclic adenosine monophosphate: (1) beta-adrenergic receptor stimulation with isoproterenol; (2) H2 receptor stimulation with dimaprit; and (3) adenylate cyclase stimulation with forskolin. METHODS: Male Sprague-Dawley rats weighing 250 to 350 g were injected with endotoxin (20 mg/kg intraperitoneal) or saline. Six hours later, the cumulative dose response to beta-adrenergic receptor stimulation (isoproterenol), H2 receptor stimulation (dimaprit), and adenylate cyclase stimulation (forskolin) was determined in isolated rat pulmonary artery and thoracic aortic rings preconstricted with phenylephrine. RESULTS: Endotoxin caused significant impairment of relaxation to isoproterenol in the pulmonary artery, but the response in the aorta was not different from the control response. In the pulmonary circulation, endotoxin converted the response to dimaprit from vasorelaxation to vasoconstriction. On the other hand, dimaprit resulted in vasorelaxation in the thoracic aorta after endotoxin; however, the response was impaired compared with the control response. Endotoxin did not affect the dose response to forskolin in either the pulmonary artery or the thoracic aorta. CONCLUSION: From these data, we conclude that endotoxin causes regional specific changes in vascular reactivity. These changes in vascular reactivity result in preserved vasorelaxation in the systemic circulation and impairment of vasorelaxation in the pulmonary circulation in response to endotoxin.

Adrenergic beta-Agonists↗
PubMed1998

Tissue-specific protein kinase C isoforms differentially mediate macrophage TNFalpha and IL-1beta production.

UNLABELLED: Macrophage subpopulations are differentially activated during sepsis, shock, or trauma; however, it is unknown whether inherent mechanistic and phenotypic differences exist between macrophage subpopulations that may account for region-specific inflammation. We hypothesized that macrophage expression/function of protein kinase C (PKC) isoforms is tissue specific (alveolar versus peritoneal). Rat alveolar and peritoneal macrophages were each probed for the expression of PKC isoforms alpha, beta1, beta2, gamma, delta, epsilon, zeta, and theta by immunoblot. PKC isoforms alpha, beta1, beta2, and zeta were detected in both populations; however, isoforms epsilon, gamma, and eta were found in alveolar macrophages only. To investigate the functional role of the Ca2+-dependent PKC (cPKC) versus Ca2+-independent PKC (nPKC) isoforms, pan-PKC isoform inhibition (cPKC and nPKC), or cPKC isoform selective inhibition (alpha, beta1, beta2, gamma) was performed before endotoxin (lipopolysaccharide, Salmonella minnesota, 100 ng/mL) stimulation in vitro. Pan-PKC isoform inhibition attenuated TNFalpha and IL-1beta production by each population; however, selective cPKC (alpha, beta1, beta2, gamma) inhibition decreased peritoneal, but not alveolar, macrophage TNFalpha production. IL-1beta production was not affected by cPKC inhibition in either population. CONCLUSIONS: 1) alveolar and peritoneal macrophages constitutively express different PKC isoforms; 2) alveolar macrophages uniquely express isoforms epsilon, gamma, eta; 3) TNFalpha production is regulated by cPKCs in peritoneal macrophages, but by nPKCs in alveolar macrophages; 4) nPKCs regulate IL-1beta production in both populations. These results suggest that tissue-specific PKC isoforms differentially mediate macrophage function, which may have important regulatory implications in the compartmentalization of immune function. Further understanding may allow region-specific manipulation of inflammation.

Animals↗