Related Experiment Videos
Role of complement in endotoxin/platelet-activating factor-induced lung injury
R Rabinovici1, C G Yeh, L M Hillegass
1Department of Surgery, Jefferson Medical College, Philadelphia, PA 19107-5083.
Insights
Recombinant human soluble C receptor-1 protects against lung injury in a rodent model of adult respiratory distress syndrome by reducing edema and neutrophil infiltration. Complement factors play a key role in this condition.
Area of Science:
- Immunology
- Pulmonary Medicine
- Complement System Research
Background:
- C receptor-1 regulates C3 and C5-convertases.
- Recombinant human soluble C receptor-1 (shC receptor-1) reduced infarct size in myocardial ischemia/reperfusion injury.
- Adult respiratory distress syndrome (ARDS) involves complex inflammatory pathways.
Purpose of the Study:
- To investigate the protective effect of shC receptor-1 on ARDS-induced pulmonary injury in a rodent model.
- To elucidate the role of complement factors in LPS/platelet-activating factor-induced lung injury.
Main Methods:
- ARDS model induced by Escherichia coli endotoxin (LPS) and platelet-activating factor (PAF).
- Administration of shC receptor-1 (10 mg/kg or 1 mg/kg) or vehicle.
- Assessment of pulmonary edema, myeloperoxidase activity, C3 and C5b-9 deposition, bronchoalveolar lavage fluid (BALF) cell counts and protein concentration, and serum TNF-alpha.
- Complement depletion using cobra venom factor (CVF).
Main Results:
- LPS/PAF induced microvascular lung injury with edema, increased BALF neutrophils and protein, and C3/C5b-9 deposition.
- Pretreatment with shC receptor-1 (10 mg/kg) significantly prevented pulmonary edema, altered BALF cell counts and protein, and attenuated C3/C5b-9 deposition.
- shC receptor-1 did not affect lung myeloperoxidase activity or serum TNF-alpha.
- CVF-induced C depletion abolished pulmonary edema and elevated BALF leukocytes but did not impact myeloperoxidase activity or TNF-alpha.
Conclusions:
- shC receptor-1 demonstrates a protective effect against LPS/PAF-induced ARDS-like pulmonary injury.
- Complement factors, particularly C3 and C5b-9, are critically involved in the pathogenesis of ARDS.
- shC receptor-1 may represent a potential therapeutic agent for ARDS.
Abstract:
C receptor-1 is a protein involved in the regulation of C3 and C5-convertases. Recombinant human soluble C receptor-1 has recently been produced and shown to reduce infarct size in a rat model of myocardial ischemia/reperfusion injury. The present study aimed to investigate whether recombinant human soluble C receptor-1 exerts any protective effect on pulmonary injury produced in a rodent model of adult respiratory distress syndrome. In this model, Escherichia coli endotoxin (LPS, 0.1 microgram/kg) combined with platelet-activating factor (1 pmol/kg/min over 60 min, n = 10) caused microvascular lung injury characterized by elevation of myeloperoxidase activity, deposition of C3 and C5b-9 on the endothelium of pulmonary vessels, and pulmonary edema. Furthermore, bronchoalveolar lavage revealed increased neutrophil count and elevated protein concentration. These pulmonary responses were associated with elevated serum TNF-alpha. Pretreatment (10 min, i.v.) with recombinant human soluble C receptor-1 at 10 mg/kg (n = 13), but not at 1 mg/kg, prevented the LPS/platelet-activating factor-induced pulmonary edema (p less than 0.01) and changes in the bronchoalveolar lavage fluid cell count (p less than 0.01) and protein concentration (p less than 0.05), and attenuated the deposition of C3 and C5b-9 to lung vessels. There was no effect on lung myeloperoxidase activity and serum TNF-alpha. Also, C depletion by cobra venom factor (500 U/kg, i.v.) eliminated the pulmonary edema and elevated leukocyte count in bronchoalveolar lavage fluid, but had no effect on lung myeloperoxidase activity and serum TNF-alpha. These data suggest that C factors may play an important role in the pathophysiology of adult respiratory distress syndrome.