PubMed Health⌕ Search

Biomedical subjects

B C Sheridan

Publications and source records attributed to B C Sheridan.

At least 19 recordsLinked to original sources
PubMed2006

Thrombin generation in vascular tissue.

BACKGROUND: Classically, it is thought that the vast majority of thrombin is generated on the surface of platelets, however, thrombotic events occur in patients despite treatment with potent antiplatelet agents. METHODS AND RESULTS: In freshly harvested left internal mammary artery (IMA) sections, addition of CaCl2 and platelet-poor plasma (PPP) were sufficient to stimulate a profound burst of thrombin and this effect was inhibited by antitissue factor antibodies. Ultracentrifugation of PPP to remove platelet microparticles had no effect on thrombin generation. Both the extrinsic and factor VIII-dependent pathways were necessary for IMA-supported thrombin generation as PPP derived from individuals deficient in factors V, VII, VIII or X did not support thrombin production. Small amounts of thrombin were generated utilizing factor IX (FIX)-deficient plasma, however, thrombin was not generated by aorta from FIX-deficient mice when FIX-deficient plasma was used. The addition of non-lipidated tissue factor (0.6 pM) and CaCl2 to actively proliferating cultured human aortic smooth muscle cells (SMC) resulted in a pronounced burst of thrombin generation occurring between 3 and 15 min after treatment. In the absence of tissue factor, thrombin was generated but at a slower rate and with a peak value 26% of that observed in the presence of tissue factor. CONCLUSION: Significant thrombin generation can occur on vascular tissue in the absence of platelets or platelet microparticles and on the surface of non-apoptotic SMC.

Aorta↗
PubMed2000

Differential inducible nitric oxide synthase expression in systemic and pulmonary vessels after endotoxin.

Inducible nitric oxide synthase (iNOS) is associated with vascular hypocontractility in systemic vessels after endotoxin lipopolysaccharide (LPS) administration. Although lung iNOS is increased after LPS, its role in the pulmonary circulation is unclear. We hypothesized that whereas iNOS upregulation is responsible for LPS-induced vascular dysfunction in systemic vessels, iNOS does not play a significant role in the pulmonary artery (PA). Using isolated aorta (AO) and PA rings, we examined the effect of nonselective NOS inhibition [N(G)-monomethyl-L-arginine (L-NMMA); 100 micromol/l] and selective iNOS inhibition (aminoguanidine, AG; 100 micromol/l) on alpha(1)-adrenergic-mediated vasoconstriction (phenylephrine; 10(-9) to 10(-3) M) after LPS (Salmonella typhimurium, 20 mg/kg ip). We also determined the presence of iNOS using Western blot and immunohistochemistry. LPS markedly impaired AO contractility (maximal control tension 1,076 +/- 33 mg vs. LPS 412 +/- 39 mg, P < 0.05), but PA contractility was unchanged (control 466 +/- 29 mg vs. LPS 455 +/- 27 mg, P > 0.05). Selective iNOS inhibition restored the AO's response to vasoconstriction (LPS + AG 1,135 +/- 54 mg, P > 0.05 vs. control and P < 0.05 vs. LPS), but had no effect on the PA (LPS + AG 422 +/- 38 mg, P > 0.05 vs. control and LPS). Western blot and immunohistochemistry revealed increased iNOS expression in the AO after LPS, but iNOS was not detected in the PA. Our results suggest that differential iNOS expression after LPS in systemic and pulmonary vessels contributes to the phenomenon of sepsis/endotoxemia-induced systemic hypotension and pulmonary hypertension.

Animals↗
PubMed1999

Interleukin-11 attenuates pulmonary inflammation and vasomotor dysfunction in endotoxin-induced lung injury.

Interleukin (IL)-11, like other members of the gp130 receptor class, possesses anti-inflammatory properties. We hypothesized that IL-11 pretreatment would attenuate endotoxin [lipopolysaccharide (LPS)]-induced lung inflammation and diminish injury to endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation that require cGMP in Sprague-Dawley rats. LPS (20 mg/kg ip) increased lung tumor necrosis factor (TNF)-alpha compared with the saline control (0.7 +/- 0.15 ng/g lung wet wt for control vs. 3.5 +/- 0.09 ng/g lung wet wt for LPS; P < 0.05). IL-11 (200 mg/kg ip) injected 10 min before LPS administration attenuated the LPS-induced lung TNF-alpha levels (1.6 +/- 0.91 ng/g lung wet wt; P < 0.05 vs. LPS). IL-11 also diminished LPS-induced lung neutrophil sequestration as assessed by myeloperoxidase units (2.1 +/- 0.25 U/g lung wet wt for saline and 15.6 +/- 2.02 U/g lung wet wt for LPS vs. 7.07 +/- 1.65 U/g lung wet wt for LPS plus IL-11; P < 0.05). Similarly, TNF-alpha binding protein (175 mg/kg) attenuated LPS-induced myeloperoxidase activity (6.04 +/- 0.14 U/g lung wet wt; P < 0.05). Both IL-11 and TNF-alpha binding protein similarly attenuated LPS-induced endothelium-dependent vasomotor dysfunction with improved relaxation responses to 10(-7) and 10(-6) M acetylcholine and A-23187 in phenylephrine-preconstricted isolated pulmonary artery rings (P < 0.05 vs. LPS). Endothelium-independent relaxation responses to sodium nitroprusside were also improved after LPS at 10(-6) M (P < 0.05 vs. LPS). Moreover, IL-11 decreased endotoxin-induced mortality in CF1 mice from 90 to 50% (P </= 0.05 vs. LPS). Therefore, IL-11 prevents LPS-induced lung TNF-alpha production, neutrophil sequestration, and pulmonary vasomotor dysfunction. We conclude that IL-11 possesses anti-inflammatory activity that protects against LPS-induced lung injury and lethality.

Acetylcholine↗
PubMed1999

Independent and combined effects of inhaled nitric oxide, liquid perfluorochemical, and high-frequency oscillatory ventilation in premature lambs with respiratory distress syndrome.

Acute lung injury caused by tidal volume ventilation in the premature lamb with respiratory distress syndrome (RDS) is characterized by progessive deterioration in gas exchange and lung inflammation. Inhaled nitric oxide (iNO) improves gas exchange and decreases lung neutrophil accumulation in premature lambs with RDS. Mechanical lung recruitment techniques such as high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV) also decrease lung injury and improve gas exchange in experimental models of neonatal respiratory failure. We hypothesized that two lung recruitment strategies (HFOV and PLV) would have similar effects on gas exchange and lung inflammation, and would augment the response to iNO. We studied the individual and combined effects of iNO, HFOV, and PLV (perflubron) in 31 extremely premature lambs (115 d, 0.78 term) using seven mechanical ventilation protocols. Four groups were treated with conventional ventilation (control CV, CV + iNO, CV + PLV, and CV + PLV + iNO). Three groups were treated with HFOV (control HFOV, HFOV + iNO, HFOV + PLV). Control CV animals had progressive deterioration in gas exchange over the 4-h study period (a/AO2 at 4 h = 0.06 +/- 0.01). In contrast, both HFOV and CV + PLV caused sustained improvements in oxygenation at 4 h (HFOV a/AO2 = 0. 27 +/- 0.06, CV + PLV a/AO2 = 0.25 +/- 0.04; p < 0.01 versus CV). Both lung recruitment strategies improved oxygenation when combined with iNO (5 ppm). Lung neutrophil accumulation was reduced by HFOV, PLV, and iNO compared to CV. We conclude that HFOV and PLV with perflubron cause similar improvements in gas exchange and lung inflammation in the premature lamb with severe RDS, and both strategies augment the oxygenation response to iNO.

Administration, Inhalation↗
PubMed1999

L-arginine attenuates endothelial dysfunction in endotoxin-induced lung injury.

BACKGROUND: Pulmonary vasorelaxation to endothelium-dependent and independent agonists is dysfunctional in endotoxin-induced acute lung injury. L-arginine is the precursor to endothelial production of nitric oxide (NO), suggesting that arginine and NO are intimately linked. We hypothesized that L-arginine would attenuate endotoxin-induced dysfunction of guanosine 3',5'-cyclic monophosphate-mediated pulmonary vasorelaxation. METHODS: Concentration-response curves were generated for acetylcholine, calcium ionophore A23187, and sodium nitroprusside (SNP) in isolated phenylepherine-preconstricted pulmonary artery rings (10(-9) to 10(-6) mol/L) 4 hours after endotoxin (500 mg/kg intraperitoneal) or saline injection. The effect of L-arginine in vitro was determined with L- or D-arginine (50 mmol/L) 30 minutes before dose response. RESULTS: Endothelium-dependent pulmonary vasorelaxation was dysfunctional after endotoxin injection as demonstrated by impaired responses to acetylcholine and A23187 (P < .05 vs control). Endotoxin-induced dysfunction of these endothelium-dependent responses was attenuated by L-arginine (P < .05 vs endotoxin). Endothelium-independent vasorelaxation (SNP) was also dysfunctional after endotoxin treatment (P < .05 vs control). L-arginine failed to attenuate the endotoxin-induced dysfunction of the response to SNP. The concentration responses for endothelium-dependent and independent vasorelaxing agonists in endotoxin-treated rats were not influenced by D-arginine. CONCLUSION: L-arginine supplementation attenuates endotoxin-induced dysfunction of endothelium-dependent pulmonary vasorelaxation.

Acetylcholine↗
PubMed1998

Acute and chronic effects of bilateral lung transplantation without cardiopulmonary bypass on the first transplanted lung.

BACKGROUND: Bilateral lung transplantation (BLT) without cardiopulmonary bypass (CPB) may exacerbate reperfusion injury to the initially engrafted lung because of increases in pulmonary flow during implantation of the second graft. METHODS: In a retrospective review of 23 BLT patients, we hypothesized that BLT without CPB injures the first transplanted lung measured by acute and late graft dysfunction compared to the second transplanted lung. Of the 23 BLT, 19 underwent transplantation without CPB while 4 patients were placed on CPB secondary to hemodynamic instability. RESULTS: Acute graft function was assessed by radiographic scoring of lung quadrants (blinded radiologist; 0 = no infiltrate; 1 = infiltrate; maximum = 2 per lung) and by arterial/alveolar oxygen tension ratios (PaO2/ FiO2) ratios. Late graft function was evaluated by quantitative perfusion scan. Lung perfusion was graded as abnormal if less than 50% on the right or less than 45% on the left (Fisher's exact). Radiographic scores were not different between first and second implanted lungs at 1 and 24 hours, PaO2/FiO2 ratios at 1 and 24 hours were 273+/-26 and 312+/-23, respectively, and perfusion scans at 3 and 12 months revealed normal differential blood flow. CONCLUSIONS: These findings suggest no acute or chronic differences occur between the first or second transplanted lung completed without CPB.

Adult↗
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↗
PubMed1998

L-arginine prevents lung neutrophil accumulation and preserves pulmonary endothelial function after endotoxin.

L-Arginine supplementation has been shown to restore endothelium-derived nitric oxide production in several pathological states. The purpose of this study was to examine the effect of administration of exogenous L-arginine on the endotoxin-induced lung neutrophil accumulation and impairment of endothelium-dependent guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pulmonary vasorelaxation in rats. Endothelium-dependent relaxation was tested by receptor-dependent [acetylcholine (ACh)] and receptor-independent (A-23187) pathways. Endothelium-independent relaxation was tested with sodium nitroprusside (SNP). In isolated pulmonary arterial rings, concentration-response curves were generated with ACh, A-23187, and SNP (10(-9) to 10(-6) M) 4 h after endotoxin (500 micrograms/kg i.p.) with and without prior administration of L-arginine (300 mg/kg i.p.). Lung neutrophil accumulation was determined by myeloperoxidase (MPO) assay. After endotoxin, lung neutrophil accumulation was significantly increased (MPO activity, 3.8 +/- 0.4 vs. 0.8 +/- 0.1 units/g lung weight in control cells; P < 0.05), which was prevented by L-arginine treatment (MPO activity, 1.3 +/- 0.3 units/g lung weight; P < 0.05 vs. endotoxin). Endotoxin produced a significant impairment of endothelium-dependent cGMP-mediated pulmonary vasorelaxation by receptor-dependent (ACh) and -independent (A-23187) pathways as well as of endothelium-independent relaxation (SNP). Prior treatment with L-arginine, but not with D-arginine, preserved endothelium-dependent vasorelaxation. Neither L- nor D-arginine influenced endotoxin-induced impairment of endothelium-independent, cGMP-mediated pulmonary vasorelaxation. We conclude that administration of exogenous L-arginine prevents endotoxin-induced lung neutrophil accumulation and attenuates its associated impairment of endothelium-dependent, cGMP-mediated pulmonary vasorelaxation.

Acetylcholine↗
PubMed1997

Hemorrhage activates myocardial NFkappaB and increases TNF-alpha in the heart.

The heart is a tumor necrosis factor (TNFalpha) producing organ. Locally (v systemically)-produced TNFalpha likely contributes to myocardial dysfunction via direct suppression of myocardial contractile function, the induction of myocardial apoptosis, and the genesis of cardiac hypertrophy. Although recent studies have demonstrated increased myocardial TNFalpha following endotoxemia, it remains unknown whether shock, in the absence of sepsis, activates myocardial nuclear factor kappa B (NFkappaB, a TNFalpha transcription factor) and/or increases TNFalpha in the heart. To study this, rats were hemorrhaged and resuscitated, after which hearts were harvested and analysed for evidence of NFkappaB activation (electrophoretic mobility shift assay) and assayed for TNFalpha levels. Hemorrhage and resuscitation activated NFkappaB and resulted in a dramatic increase in myocardial TNFalpha. This study constitutes the initial demonstration that hemorrhagic shock activates the signaling mechanisms which culminate in increased myocardial TNFalpha. Indeed, this may have important clinical implications, since hemorrhage is a frequent complication of both iatrogenic and accidental trauma, as well as a potent instigator of multiple organ failure.

Animals↗
PubMed1997

Alpha-adrenergic activation of myocardial NF kappa B during hemorrhage.

Hemorrhage and resuscitation has been recognized as an exclusively destructive process which results in multiple organ dysfunction. Although it is well established that endogenous adaptation (preconditioning) mechanisms exist, it is unknown whether hemorrhage and resuscitation induces endogenous adaptive/protective mechanisms in the heart. Furthermore, alpha 1-adrenoceptors and nuclear factor kappa B (NF kappa B) have each been implicated in stress-induced signal transduction; however, whether they might be involved in hemorrhage-induced adaptive signal transduction remains unknown. This study tests the hypothesis that H/R activates myocardial NF kappa B and results in myocardial adaptation via alpha 1-adrenoceptors. Rats were briefly (10 min) hemorrhaged to 35 mmHg and resuscitated, sham operated, or neither, with and without prior alpha 1-adrenoceptor inhibition (prazosin). Hearts were then isolated and either probed for NF kappa B activation or subjected to a second insult consisting of global normothermic I/R (20 min/40 min). Antecedent hemorrhage and resuscitation activated myocardial NF kappa B and improved left ventricular developed pressure, coronary flow, and end diastolic pressure following ischemia-reperfusion (P < 0.05, ANOVA with Bonferroni-Dunn). Hemorrhage-induced adaptation was abolished by prior alpha 1-adrenoceptor blockade. This study constitutes the initial demonstration that H/R activates myocardial NF kappa B and induces adaptive signal transduction against ischemia-reperfusion injury.

Adrenergic alpha-Antagonists↗
PubMed1997

Protein kinase C isoform diversity in preconditioning.

Protein kinase C (PKC) appears to be a common intracellular effector and signal collector during cardiac preconditioning; however, it remains unknown whether agonists that activate different PKC isoforms are also linked to select aspects of myocardial protection. Using agonists that are known to activate unique combinations of PKC isoforms, we interrogated the relationship between isoform activation and the different aspects (pH, function, and viability) of endogenous myocardial protection. To study this, isolated rat hearts were subjected to ischemia-reperfusion (I/R) (20 min/40 min), without (control = Ctrl) or with receptor-dependent [phenylephrine (PE), 50 microM; adenosine (ADO), 125 microM] or -independent [phorbol myristate acetate (PMA), 100 nM] activation of PKC. Function, pH, and viability were assessed by rate pressure product (%RPP) and coronary flow (CF; ml/min), by 31P NMR, and by CF creatine kinase (CK; U/liter) leak, respectively. PMA, which activates PKC delta but not eta, resulted in intracellular pH (pHi) and viability protection, but did not protect against postischemic myocardial stunning. ADO, which activates PKC eta but not delta, protects against stunning, but not acidosis or necrosis. PE, which activates PKC delta and eta, provided global myocardial protection against necrosis, acidosis, and stunning. Different PKC isoforms may be linked to distinct aspects of myocardial protection. Targeted activation of PKC isoforms may allow precise mechanistic application of preconditioning-like myocardial protection.

Animals↗
PubMed1997

Phosphodiesterase inhibition overcomes pulmonary vasomotor dysfunction in acute lung injury.

Production of cGMP is impaired in endotoxin-induced acute lung injury. This results in dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation and, therefore, pulmonary hypertension. We hypothesized that cyclic nucleotide phosphodiesterase (PDE) inhibition would attenuate endotoxin-induced impairment to cGMP-mediated mechanisms of pulmonary vasorelaxation. The purpose was to examine the effect of stimulating cGMP production with concurrent inhibition of cGMP catabolism by PDE inhibition following endotoxin-induced acute lung injury. Isolated pulmonary arterial rings from rats (n = 5) were studied 6 hrs after endotoxin (20 mg/kg ip) or saline. In a third group (n = 5), PDE inhibition was accomplished with in vitro 3-isobutyl-1-methylxanthine (IBMX, 1 microM for 30 min). Cyclic GMP-mediated relaxation was interrogated by stimulating (1) endothelium-dependent mechanisms with the receptor-dependent agonist acetylcholine and the receptor-independent agonist A23187, a calcium ionophore, and an (2) endothelium-independent mechanism with sodium nitroprusside. PDE inhibition attenuated endotoxin-induced vasomotor dysfunction. A two-pronged approach-stimulating cGMP production and preventing cGMP catabolism with PDE inhibition-may offer a therapeutically accessible mechanism to overcome vasomotor dysfunction in acute lung injury.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Pentoxifylline treatment attenuates pulmonary vasomotor dysfunction in acute lung injury.

Acute lung injury (ALI) is characterized by pulmonary hypertension. Although the pathophysiology of ALI is complex, cytokine production, especially tumor necrosis factor-alpha (TNF-alpha), is known to mediate histologic lung injury. Pentoxifylline (PTX) is known to inhibit the expression of many cytokines, including TNF-alpha. The purpose of this study was to determine the effect of PTX treatment on endotoxin-induced impairment of endothelium-dependent mechanisms of pulmonary vasorelaxation. Mechanisms of endothelium-dependent relaxation were studied with the muscarinic receptor agonist, acetylcholine (ACh), and the receptor-independent calcium ionophore, A23187. Endothelium-independent pulmonary vasorelaxation was examined by direct stimulation of smooth muscle guanylate cyclase with the nitric oxide donor, sodium nitroprusside (SNP). Five rats received PTX (50 mg/kg) and endotoxin (20 mg/kg), endotoxin alone, or saline ip. After 6 hr, dose-response curves to ACh, A23187, and SNP were determined in isolated pulmonary artery rings preconstricted with phenylephrine (PE). PTX attenuated but did not eliminate endotoxin-induced impairment of endothelium-dependent and -independent pulmonary vasorelaxation. These data suggest that PTX may offer a therapeutic modality for the treatment of pulmonary hypertension in ALI.

Animals↗
PubMed1997

Neutrophils mediate pulmonary vasomotor dysfunction in endotoxin-induced acute lung injury.

BACKGROUND: The major hemodynamic feature of endotoxin (ETX)-induced acute lung injury is pulmonary hypertension secondary to increased pulmonary vascular resistance. Endotoxin causes dysfunction of pulmonary vasorelaxation, which is associated with increased lung neutrophil accumulation. We hypothesized that neutrophils mediate the dysfunction of cGMP-mediated pulmonary vasorelaxation in acute lung injury. In a rat model of ETX-induced lung injury, our purpose was to determine the effect of neutrophil depletion on the following mechanisms of pulmonary vasomotor control: endothelium-dependent cGMP-mediated relaxation (response to acetylcholine) and endothelium-independent relaxation (response to sodium nitroprusside). METHODS: Rats were studied 6 hours after ETX (20 mg/kg). Neutropenia (< 75 neutrophils/microL) was induced with anti-neutrophil serum 24 hours before ETX. Saline injected rats were controls. Dose-response curves to acetylcholine and sodium nitroprusside were generated in isolated pulmonary artery rings preconstricted with phenylephrine (n = 10 rings/5 rats per group). Lungs were harvested (n = 4 rats/group) and lung neutrophil accumulation was assessed with a myeloperoxidase assay. RESULTS: Endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation was dysfunctional in ETX-induced ALI. Neutrophil depletion prevented lung neutrophil accumulation and attenuated pulmonary vasomotor dysfunction after endotoxin. CONCLUSIONS: These data suggest that neutrophils contribute to pulmonary endothelium and smooth muscle dysfunction in acute lung injury induced by endotoxemia.

Acetylcholine↗
PubMed1997

L-arginine decreases alveolar macrophage proinflammatory monokine production during acute lung injury by a nitric oxide synthase-dependent mechanism.

BACKGROUND: Recent clinical reports indicate that inhaled nitric oxide (NO) reduces lung parenchymal inflammation during acute lung injury; however, the mechanism of its protective effects remains incompletely understood. We hypothesized that the provision of substrate for local NO production (L-arginine) would reduce alveolar macrophage proinflammatory monokine production during endotoxin (ETX)-induced acute lung injury. Our purposes were to (1) determine alveolar macrophage tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) production after ETX-induced acute lung injury; (2) determine the effect of L-arginine on alveolar macrophage TNFalpha and IL-1beta production in ETX-induced acute lung injury; and (3) determine whether L-arginine's effects on the alveolar macrophage are mediated by NO. METHODS: Rats received ETX (0.5 mg/kg intraperitoneal (i.p.)) or vehicle, with or without (1) L-arginine supplementation (300 mg/kg i.p.) and (2) nitric oxide synthase inhibition (N(G)-monomethyl-L-arginine, 30 mg/kg i.p.). Four hours later, alveolar macrophage were harvested by bronchoalveolar lavage and incubated at 10(6) cells/mL + 1 microg/mL phorbol myristase acetate for 24 hours. Cell-free supernatants were collected and assayed (enzyme-linked immunosorbent assay) for TNFalpha and IL-1beta. RESULTS: Sublethal ETX increased alveolar macrophage capacity to produce TNFalpha and IL-1beta (p < 0.05, analysis of variance and Bonferroni/Dunn). L-Arginine decreased alveolar macrophage TNFalpha and IL-1beta release during acute lung injury. Concurrent inhibition of nitric oxide synthase abrogated L-arginine's protective effects, suggesting that L-arginine's anti-inflammatory effects are mediated by NO. CONCLUSIONS: (1) L-Arginine is an immunomodulating nutritional supplement; (2) L-arginine decreases alveolar macrophage proinflammatory monokine production during ETX-induced acute lung injury by a nitric oxide synthase-dependent mechanism; and (3) the provision of exogenous substrate for local NO production may reduce inflammation during acute lung injury.

Analysis of Variance↗