Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs.

BACKGROUND: Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. METHODS: The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 µg/g), PMA 4 µg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. RESULTS: PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. CONCLUSIONS: Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA-induced lung injury. ATP is beneficial, while PARP plays a deteriorative effect on the PMA-induced ALI. NAC exerts protective effects on the inflammatory cascade leading to pulmonary injury. This B complex compound may be applied for clinical usage and therapeutic regimen.

Effects of phorbol myristate acetate and sivelestat on the lung injury caused by fat embolism in isolated lungs.

BACKGROUND: Fat embolism syndrome (FES) associated with acute lung injury (ALI) is a clinical condition following long bone fracture. We have reported 14 victims due to ALI with FES. Our laboratory has developed an animal model that produced fat emboli (FE). The major purpose of this study was to test whether neutrophil activation with phorbol myristate acetate (PMA) and inhibition with sivelestat (SVT) exert protection on the lung. METHODS: The lungs of Sprague-Dawley rats were isolated and perfused. FE was produced by addition of corn oil micelles into the lung perfusate. PMA and SVT were given simultaneously with FE. Parameters such as lung weight/body weight ratio, LW gain, exhaled nitric oxide (NO), protein concentration in bronchoalveolar lavage relating to ALI were measured. The neutrophil elastase (NE), myeloperoxidase, malondialdehyde and phopholipase A2 activity were determined. We also measured the nitrate/nitrite, methyl guanidine (MG), and cytokines. Pulmonary arterial pressure and microvascular permeability were assessed. Lung pathology was examined and scored. The inducible and endothelial NO synthase (iNOS and eNOS) were detected. RESULTS: FE caused ALI and increased biochemical factors. The challenge also resulted in pulmonary hypertension and increased microvascular permeability. The NE appeared to be the first to reach its peak at 1 hr, followed by other factors. Coadministration with PMA exacerbated the FE-induced changes, while SVT attenuated the effects of FE. CONCLUSIONS: The FE-induced lung changes were enhanced by PMA, while SVT had the opposite effect. Sivelestat, a neutrophil inhibitor may be a therapeutic choice for patients with acute respiratory distress syndrome (ARDS) following fat embolism.

Exercise training attenuates septic responses in conscious rats.

PURPOSE: To evaluate the effects of exercise training on the changes induced by endotoxin in arterial pressure, heart rate (HR), blood cells, biochemical factors, plasma nitrite/nitrate, methyl guanidine (MG), proinflammatory cytokines, and pathology of the heart, liver, and lung. METHODS: Twenty-four 10-wk-old male Wistar-Kyoto rats weighing 320-350 g were randomly assigned into two groups. The exercise-trained group (Tr; N = 12) received exercise training for 4 wk. The control (Con) group was placed on the treadmill and remained sedentary for the same time period. Endotoxemia was induced by intravenous (i.v.) infusion of lipopolysaccharide (LPS; 10 mg.kg(-1)) for 20 min, after which the animals were observed for 72 h. The femoral artery was cannulated to monitor arterial pressure and HR. Blood samples were collected 1 h before and at various times after LPS infusion. We determined plasma nitrite/nitrate, MG, white blood cells, neutrophils, lymphocytes, red blood cells, blood urea nitrogen, creatinine (Cr), aspartate aminotransferase, alanine aminotransferase, lactic acid dehydrogenase, creatine phosphokinase, amylase, lipase, tumor necrosis factor(alpha), and interleukin-1(beta). The heart, liver, and lung were taken for pathological examination and assessment after the experiment. RESULTS: The Tr group had lower basal levels of arterial pressure, HR, MG, neutrophils, and Cr than the Con group. Exercise training attenuated the LPS-induced decreases in blood cells. After LPS administration, plasma levels of nitrate/nitrite, MG, biochemical factors, and proinflammatory cytokines in the Con group were higher than in the Tr group. Pathological examination and assessment revealed that cardiac, hepatic, and pulmonary injury were more severe in the Con group than in the Tr group. CONCLUSIONS: Exercise training attenuates septic responses and protects organs from damage in sepsis.