Effects of inducible nitric oxide synthase and xanthine oxidase inhibitors on SEB-induced interstitial pneumonia in mice.

The authors have previously reported that intratracheal instillation of staphylococcal enterotoxin-B (SEB) induced interstitial pneumonia (IP) in autoimmune-prone mice. SEB-reactive T-cells were critically involved in the development of IP in this model. Concern has arisen about the hazards of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the process of lung injury and fibrosis. Therefore, the involvement of nitric oxide (NO) and superoxide anion (O2-) in the pathogenesis of IP in this autoimmune-prone model has been investigated. Nitrite/nitrate levels were increased in bronchoalveolar lavage (BAL) fluid and serum from SEB-injected mice. The signal of the NO-(N-(dithiocarboxy) sarcosine)2-Fe2+ complex was detected in the SEB-injected lung and whole blood by electron paramagnetic resonance (EPR) spectroscopy. NO production was significantly decreased by aminoguanidine (AG) treatment. Xanthine oxidase (XO) activity in the lung, BAL fluid, and plasma was increased with instillation of SEB, and 4-amino-6-hydroxypyrazolo(3,4-d)-pyrimidine (AHPP) significantly inhibited XO activity. Moreover, both AG and AHPP significantly decreased production of pro-inflammatory cytokines, numbers of infiltrated cells in BAL fluid, and the area of thickened alveolar septa in the SEB-injected lung. In conclusion, the overproduction of nitric oxide and super oxide anion were implicated in the pathogenesis of interstitial pneumonia, and inducible nitric oxide synthase and xanthine oxidase inhibitors had protective effects against interstitial pneumonia in this model.

Hyperoxia-induced acute lung injury using a pig model: correlation between MR imaging and histologic results.

PURPOSE: To correlate MR imaging findings with pathology in experimental hyperoxia-induced acute lung injury, which has similar pathology to diffuse alveolar damage (DAD). MATERIALS AND METHODS: Seventeen Yorkshire pigs were studied. These animals were exposed to more than 80% oxygen for 24, 48, 72, and 96 hours in a sealed cage. The lungs were removed and inflated with air infused through the trachea, and then examined by both MRI and high-resolution CT (HRCT). T1-weighted spin-echo (T1WSE), T2-weighted fast (T2WFSE), and half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequences were performed. RESULTS: Severity in MR findings and signal-to-noise ratios (SNR) on MR images were well correlated with pathological scores. CT values were also correlated well with pathologic scores. Abnormal SNR values were obtained from a pathological score of 5, whereas abnormal CT values were obtained from a pathological score of 15. Furthermore, significant differences in SNR were observed in each histopathological phase. CONCLUSION: SNRs on MR images were superior to CT values in detecting early pathologic changes in DAD. MR study also is potentially useful for evaluation of the histopathological phases in acute lung injury.

Expression of matrix metalloproteinases in pigs with hyperoxia-induced acute lung injury.

The aim of this study was to determine the role of matrix metalloproteinases (MMPs) in the pathogenesis of acute lung injury induced by hyperoxia. Twenty-three pigs were exposed in sealed cages to >80% oxygen (for 24-120 h) or room air. Correlation between MMP-2/MMP-9 activity, measured by gelatin zymography in bronchoalveolar lavage fluid (BALF), and the histological findings and pathological parameters were examined in detail. Sources of these MMPs in the hyperoxic lung were analysed by immunohistochemistry. The histological progression of acute lung injury in this model ranged from the early exudative to the early proliferative phase of diffuse alveolar damage (DAD). MMP-2 and -9 activities were elevated under prolonged hyperoxic exposure. MMP-9 activity correlated significantly with the oxygen tension in arterial blood/inspiratory oxygen fraction, the lung wet-to-dry weight ratio, and the number of neutrophils in BALF, whereas MMP-2 activity did not correlate at all with these factors. MMP-9 activity correlated more closely with the pathological findings of DAD than did MMP-2 activity. Strong MMP-9 expression was observed in neutrophils, alveolar macrophages as well as alveolar lining epithelial cells. These results suggest that matrix metalloproteinase. which may derive from neutrophils recruited into airspaces, plays an important role in the pathogenesis of hyperoxic diffuse alveolar damage

Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias.

Destruction of subepithelial basement membrane is a key event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). To evaluate the role of matrix metalloproteinases (MMPs) in parenchymal remodeling in idiopathic interstitial pneumonia (IIP), we studied MMP-2 and -9 activity, in bronchoalveolar lavage fluid (BALF) by zymography and the expression of MMP-2 and -9 and TIMP-2 in lung tissue by immunohistochemistry. BALF and lung tissues were collected from 26 patients with usual interstitial pneumonia (IPF-UIP), 11 with nonspecific interstitial pneumonia (NSIP), and 6 with bronchiolitis obliterans organizing pneumonia (BOOP). IPF-UIP cases showed predominant expression of MMP-9, whereas NSIP and BOOP cases showed predominant MMP-2 expression in BALF and in tissues. In BALF samples from rapidly progressive IPF-UIP cases, neutrophil-derived MMP-9 activity, as well as MMP-9 active form were characteristically detected. Furthermore, the MMP-9 activity correlated significantly with an increase of neutrophils in BALF, whereas the MMP-2 activity associated with NSIP and BOOP correlated with an increase of lymphocytes. These results indicate that MMP-9 in IPF-UIP and MMP-2 in NSIP and BOOP may contribute to pulmonary structural remodeling through type IV collagenolytic activity. The characteristic contributions of matrix-degrading proteins may relate to the distinct prognostic features of these diseases.

Hyperoxia-induced diffuse alveolar damage in pigs: correlation between thin-section CT and histopathologic findings.

PURPOSE: To determine whether lung abnormalities at thin-section computed tomography (CT) in experimental hyperoxic lung injury correlate with the pathologic phases of diffuse alveolar damage (DAD). MATERIALS AND METHODS: Eighteen juvenile pigs were exposed to more than 80% oxygen-for 24, 48, 72, 96, or 120 hours-or room air in sealed cages. Their removed lungs were inflated with air infused through the trachea and examined with thin-section CT. Two independent observers, without knowledge of the exposure times, compared 63 areas selected on the CT scans with the corresponding pathologic and histologic findings, which were evaluated independently by two pathologists. RESULTS: CT findings correlated well with histologic findings (rho = 0.86, P <.001), which corresponded to the pathologic phases of DAD. All areas of normal CT attenuation, eight of nine spared regions within areas of opacity, and two of 15 areas of ground-glass opacity corresponded to the early exudative pathologic phase of DAD. All areas that showed traction bronchiolectasis at CT corresponded to the early proliferative pathologic phase. There was good observer agreement regarding the interpretation of CT findings (kappa statistic, >0.60) and histologic results (>/=0.70). CONCLUSION: Thin-section CT findings reflect the pathologic phases of DAD, although the early exudative phase cannot be specifically depicted by thin-section CT. Traction bronchiolectasis on a CT scan suggests progression to the proliferative phase.

Effects of granulocyte and granulocyte-macrophage colony-stimulating factors in a neutropenic murine model of trichosporonosis.

We produced disseminated trichosporonosis in a neutropenic murine model with Trichosporon asahii, which was identified by DNA relatedness analysis. We then assessed the efficacy of granulocyte colony-stimulating factor (G-CSF) (30 to 100 microg/kg of body weight per day) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.8 to 2 microg/kg x day). The administration of G-CSF either before or after infection improved the survival rate from less than 25% up to 100% (P < 0.05). The effects of G-CSF on organ clearance and histological examinations were most remarkable in the lungs. The levels of tumor necrosis factor alpha (TNF-alpha) in bronchoalveolar lavage fluid (BALF) of neutropenic and G-CSF-pretreated mice were 60 +/- 6 ng/ml and 18 +/- 6 pg/ml, respectively, at 24 h after infection. Immunohistologically, alveolar macrophages proved to be the main source of TNF-alpha in BALF. GM-CSF increased neutrophil counts less significantly than did G-CSF and increased the lethality (P < 0.05) with a high level of TNF-alpha in BALF. Expecting to inhibit TNF-alpha, we administered anti-TNF-alpha intraperitoneally at the dose completely inhibiting TNF-alpha in plasma (2 x 10(4) U), but the TNF-alpha level in BALF and the lethality increased. Though the number of neutrophils at the early stage of infection appeared to be the most critical, the results suggest that other host defense mechanisms, such as TNF-alpha overproduction in the lungs, have an important role in the prognosis of trichosporonosis.

Prolonged isoflurane anesthesia in a case of catastrophic asthma.

A 13-year-old female patient with life-threatening asthma was treated with the inhalational anesthetic agent, 1% isoflurane, for 202 h (140 minimum alveolar concentration (MAC) hours). The patient survived and exhibited no significant side effects attributable to the medication. The present patient report provides additional clinical information supporting the utilization of long-term isoflurane general anesthesia in the management of refractory status asthmaticus that have not responded to aggressive medical management.