Clusterin Protects the Lung from Leukocyte-Induced Injury

Abstract

Clusterin (CLU) is a multifunctional 75- to 80-kDa glycoprotein that is upregulated during cellular stress and might represent a defense mechanism during local cellular damage. Mechanisms discussed are antiapoptotic, antioxidative, and anticomplement properties as well as chaperone-like features protecting stressed proteins. The aim of this study was to investigate potential protective effects of CLU on pulmonary vasculature after in situ PMN activation in isolated rabbit lungs. The experiments were performed on 24 isolated and ventilated rabbit lungs that were perfused with 200 mL of Krebs-Henseleit-10% blood buffer with a constant flow of 150 mL/min in a recirculating system. It was tested whether pretreatment with CLU (2.5 microg/ml; n = 8) or catalase (CAT, 5000 U/ml; n = 8) before N-formyl-Met-Leu-Phe (fMLP; 10(-8) M) injection influenced pulmonary artery pressure (PAP) peak airway pressures (PAW) and edema formation as compared with controls (n = 8). Baseline values of PAP were 9-11 mmHg and PAW 11-13 cm H2O. Application of fMLP resulted in an acute significant (P < 0.01) increase of PAP (48 +/- 29 mmHg) within 2 min in the control group and PAW increased to 35 +/- 7 cm H2O within 30 min. Pretreatment with CLU completely suppressed the PAP and PAW response as a result of the fMLP challenge (P < 0.001), whereas a transient PAW increase up to 27 +/- 15 mmHg was observed after CAT. Complement factor C3a release was suppressed by CAT, whereas CLU blocked the complement cascade at the level of C5b-9 formation. Moreover, generation of thromboxane A(2) was reduced after CLU and CAT. Lung edema occurred in the fMLP group but was absent (P < 0.001) after CLU and CAT treatment. Both CLU and CAT prevented fMLP-induced lung injury. Stabilizing effects of CLU, point towards complement regulating features at the level of the terminal complement sequence. Elevated levels of CLU during inflammation could reflect a compensatory organ protective mechanism. Further studies are required to elucidate the clinical impact of the observed organ-protective properties of CLU.

Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung

“…Haemodynamic reactions of the isolated rabbit lungs were in line with our previous data [18], which showed increases of PAP and oedema formation after LPS challenge compared with non-LPS-treated lungs due to an overweighing of vasoconstrictive pro-inflammatory mediators [16,17]. Within 2 h, pulmonary hypertension up to 20.8 6 2.9 mmHg (Fig.…”

“…Haemodynamic data and lung oedema Following a 30 min steady-state phase, baseline values of PAP ranged between 8 and 11 mmHg in all groups (airway pressure 6-8 cm H 2 O), according to previous data [16][17][18]. Inflammatory stimulation with LPS increased PAP (Fig.…”

“…The techniques of preparing and perfusing isolated rabbit lungs have been previously described in detail [16][17][18]. After approval by the local board for animal protection, female chinchilla rabbits (Orticolagus caniculus) weighing 2100 6 196 g (mean 6 standard deviation) were anaesthetized with ketamine (50 mg kg 21 ) and xylazine (4 mg kg 21 ) and anticoagulated with heparinsodium 1000 U kg 21 , injected in the ear vein.…”

The Stress Response of the Exocrine Pancreas

“…PAP-1 [18] and clusterin [Savkovic´, in preparation] display anti-infl ammatory features in the exocrine pancreas. Both molecules seem to be able to diminish systemic complications of pancreatitis like leukocyte-induced lung injury [11,35] . p8 infl uences a great number of stress-induced genes at the transcriptional level [26] .…”

“…In addition, clusterin seems to be able to attenuate systemic complications of acute pancreatitis. For example clusterin is able to protect the lung from leukocyte-induced lung injury [35] . Therefore, clusterin has anti-apoptotic and anti-infl ammatory function in the exocrine pancreas.…”