Receptor for advanced glycation end products is associated with systemic and organ-specific severity of acute lung injury and acute respiratory distress syndrome

Introduction

Receptor for advanced glycation end products (RAGE) is an acute phase inflammatory mediator primarily expressed by alveolar type I cells in the lung. The association between circulating RAGE and severity of acute lung injury and acute respiratory distress syndrome (ALI/ARDS) has been recently suggested by both experimental and human studies. The purpose of our study is to study the significance of plasma RAGE levels over time and of bronchoalveolar lavage fluid (BALf ) RAGE in ALI/ARDS patients.

Methods

We enrolled 21 patients admitted to a single general ICU of a university-affiliated hospital affected by ALI/ARDS (1994 Consensus Conference criteria). We measured plasma RAGE levels twice on the first 2 days from intubation, then every 3 days for the first month and then once a week, until ICU discharge or death (n = 188). We also measured RAGE levels in BALf obtained by means of a standardized technique when clinically indicated (n = 22). At each sampling time we recorded data on ventilator settings, gas exchange, organ function and blood cell counts.

Results

Day 1 plasma RAGE levels (normal values <170 pg/ml) were high (median 1,588 pg/ml, IQR 780 to 2,398 pg/ml) and then lowered over time. When all samples were considered, plasma RAGE levels were significantly higher in patients with blood platelet count <100 × 10³/μl, with plasma creatinine level ≥2 mg/dl and with SOFA score ≥5 (P = 0.029, P = 0.001 and P = 0.045, respectively). Plasma RAGE increased also with the number of organ failures (P = 0.004). Moreover, circulating RAGE was significantly higher in patients with PaO₂/FiO₂ <150 and with PEEP ≥10 cmH₂O (P = 0.045 and P < 0.001, respectively). RAGE was present in BALf (median 174 pg/ml, IQR 46 to 1,476 pg/ml). Interestingly, plasma and BALf RAGE levels were not correlated (P = 0.2). BALf RAGE was significantly higher in patients with PaO₂/FiO₂ <150 mmHg and with administered tidal volume:ideal body weight ratio >6 ml/kg (P = 0.021 and P = 0.009, respectively). Patients with culture-positive BALf had higher BALf RAGE levels in comparison with culture-negative BALf (P = 0.014).

Conclusions

In ALI/ARDS patients, circulating RAGE is high on day 1, decreases over time and may be related to systemic and lung injury severity. BALf RAGE obtained from these patients may be associated with lung dysfunction and infection.