Adult respiratory distress syndrome as a severe immune reconstitution disease following the commencement of highly active antiretroviral therapy.

We report a patient who developed adult respiratory distress syndrome (ARDS) secondary to Mycobacterium tuberculosis as an immune reconstitution disease. This complication occurred 14 days after the commencement of highly active antiretroviral therapy (HAART) for advanced HIV infection. The case emphasises that immune reconstitution can be an extremely aggressive complication of HAART.

The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats.

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease. In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg x kg(-1) x day(-1)) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline. In animals given bleomycin and drug vehicle, total lung collagen was increased by 182+/-11% (mean+/-SEM) compared with saline controls at 14 days (p<0.001). The increase in lung-collagen accumulation was reduced by 75+/-12% (p<0.01) in animals given SDZ RAD and was accompanied by a concomitant 56+/-6% (p<0.001) reduction in lung weight. SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.

Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis.

Dramatic activation of the coagulation cascade has been extensively documented for pulmonary fibrosis associated with acute and chronic lung injury. In addition to its role in hemostasis, thrombin exerts profibrotic effects via activation of the major thrombin receptor, protease-activated receptor-1. In this study, we examined the effect of the direct thrombin inhibitor, UK-156406 on fibroblast responses in vitro and on bleomycin-induced pulmonary fibrosis in rats. UK-156406 significantly inhibited thrombin-induced fibroblast proliferation, procollagen production, and connective tissue growth factor (CTGF) mRNA levels when used at equimolar concentration to the protease. Thrombin levels in bronchoalveolar lavage fluid and expression of thrombin and protease-activated receptor-1 in lung tissue were increased after intratracheal instillation of bleomycin. The characteristic doubling in lung collagen in bleomycin-treated animals (38.4 +/- 2.0 mg versus 17.1 +/- 1.4 mg, P < 0.01) was preceded by significant elevations in alpha1(I) procollagen and CTGF mRNA levels (3.0 +/- 0.4-fold and 6.3 +/- 0.4-fold respectively, (P < 0.01), and total inflammatory cell number. UK-156406, administered at an anticoagulant dose, attenuated lung collagen accumulation in response to bleomycin by 35 +/- 12% (P < 0.05), inhibited alpha1(I) procollagen and CTGF mRNA levels by 50% and 35%, respectively (P < 0.05), but had no effect on inflammatory cell recruitment. This is the first report showing that direct thrombin inhibition abrogates lung collagen accumulation in bleomycin-induced pulmonary fibrosis.

Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome.

The fibroproliferative phase of acute respiratory distress syndrome (ARDS) has traditionally been regarded as a late event but recent studies that suggest increased lung collagen turnover within 24 h of diagnosis challenge this view. We hypothesized that fibroproliferation is initiated early in ARDS, characterized by the presence of fibroblast growth factor activity in the lung and would relate to clinical outcome. Patients fulfilling American/European Consensus Committee criteria for ARDS and control patients ventilated for non-ARDS respiratory failure underwent bronchoalveolar lavage (BAL) and serum sampling within 24 h of diagnosis and again at 7 d. The ability of BAL fluid (BALF) to stimulate human lung fibroblast proliferation in vitro was examined in relation to concentrations of N-terminal peptide for type III procollagen (N-PCP-III) in BALF/serum and clinical indices. At 24 h, ARDS lavage fluid demonstrated potent mitogenic activity with a median value equivalent to 70% (range 31-164) of the response to serum, and was significantly higher than control lavage (32% of serum response, range 11-42; p < 0.05). At 24 h, serum N-PCP-III concentrations were elevated in the ARDS group compared with control patients (2.8 U/ml; range 0.6-14.8 versus 1.1 U/ml; range 0.4-3.7, p < 0.0001) as were BALF N-PCP-III concentrations (2.9 U/ml; range 0. 6-11.4 versus 0.46 U/ ml; range 0.00-1.63, p < 0.01). In addition, BALF N-PCP-III concentrations at 24 h were significantly elevated in nonsurvivors of ARDS compared with survivors (p < 0.05). At 7 d, the mitogenic activity remained elevated in the ARDS group compared with control (p < 0.05) and was also significantly higher in ARDS nonsurvivors compared with survivors (67%; range 45-120 versus 31%; range 16-64, p < 0.05). These data are consistent with the hypothesis that fibroproliferation is an early response to lung injury and an important therapeutic target.

Thrombin.

Thrombin is a multifunctional serine protease which plays a central role in haemostasis by regulating platelet aggregation and blood coagulation. It is formed from its precursor prothrombin following tissue injury and converts fibrinogen to fibrin in the final step of the clotting cascade. It also promotes numerous cellular effects including chemotaxis, proliferation, extracellular matrix turnover and release of cytokines. These actions of thrombin on cells have been implicated in tissue repair processes and in the pathogenesis of inflammatory and fibroproliferative disorders such as pulmonary fibrosis and atherosclerosis. Thrombin mediates its cellular effects by proteolytically activating cell surface receptors. Presently, two such receptors have been described and their roles in regulation of these functions are currently being investigated. The discovery of multiple thrombin receptors creates the possibility of selective receptor blockade of specific thrombin mediated events. New drugs with these actions should add to our current repertoire of thrombin inhibitors used to treat thrombotic diseases.

Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats.

Previous evidence suggests a role for endothelin-1 (ET-1) in the pathogenesis of pulmonary fibrosis. To determine if ET-1 regulates collagen deposition in pulmonary fibrosis, we examined the effect of the non-selective ETA and ETB receptor antagonist bosentan (Ro 47-0203), and a selective ETA receptor antagonist, BQ-485, on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Lung collagen content, derived from measurements of hydroxyproline and expressed as mg collagen/lung, was increased in the bleomycin-treated animals by day 7 (bleomycin, 22.88+/-1.46; control 18.50+/-0.98; P<0.05), continued to increase up to day 14 (bleomycin, 38.80+/-2.17; control 22.57+/-0.77; P<0.001) and then remained constant to 21 days. Daily treatment by gavage with bosentan (100 mg/kg) did not prevent the increase in collagen deposition induced by instillation of bleomycin at any of the times measured. Continuous administration of BQ-485, by subcutaneously implanted minipump (7.5 mg/day), also failed to prevent the bleomycin-induced collagen deposition at 14 days. These findings suggest that ET-1 does not modulate collagen deposition during the development of bleomycin-induced pulmonary fibrosis. Further studies are required to assess whether endothelin receptor antagonists modulate other components of the fibrotic response or play a role in man.

Effects of GABAA receptor ligands on noradrenaline concentration and beta-adrenoceptor binding in mouse cerebral cortex.

The present experiments investigated changes in beta-adrenoceptor binding and noradrenaline stores in mouse cerebral cortex after single treatments with drugs which bind to the GABAA receptor but which attenuate the actions of GABA. Neither the GABA antagonist, securinine, nor the picrotoxin/Cl- channel ligand, picrotoxin, affected noradrenaline levels or beta-adrenoceptor binding. However, both the benzodiazepine inverse agonist, DMCM, and pentylenetetrazole increased noradrenaline levels 24 h after injection. Only pentylenetetrazol modified beta-adrenoceptor binding: there was a significant increase in receptor number 4 days after injection, but a significant decrease after 7 days. The anxiogenic, proconvulsant drug, yohimbine, was without effect. The changes induced by DMCM and pentylenetetrazole do not seem to be related to the behavioural effects of these drugs or to their affinity for binding to benzodiazepine receptors. The possibility that these compounds have actions in addition to those at the GABAA receptor is discussed.