Platelet-activating factor mediates acid-induced lung injury in genetically engineered mice

Abstract

Adult respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and the molecular mechanisms underlying it are poorly understood. Acid aspiration-induced lung injury is one of the most common causes of ARDS, characterized by an increase in lung permeability, enhanced polymorphonuclear neutrophil (PMN) sequestration, and respiratory failure. Here, we investigated the role of platelet-activating factor (PAF) and the PAF receptor (PAFR) gene in a murine model of acid aspiration-induced lung injury. Overexpression of the PAFR gene in transgenic mice enhanced lung injury, pulmonary edema, and deterioration of gas exchange caused by HCl aspiration. Conversely, mice carrying a targeted disruption of the PAFR gene experienced significantly less acid-induced injury, edema, and respiratory failure. Nevertheless, the efficiency of PMN sequestration in response to acid aspiration was unaffected by differences in PAFR expression level. The current observations suggest that PAF is involved in the pathogenesis of acute lung injury caused by acid aspiration. Thus, inhibition of this pathway might provide a novel therapeutic approach to acute lung injury, for which no specific pharmaceutical agents are currently available.

Figure 1

The time course of response in lung elastance (EL) in HCl- and saline-treated groups (n = 3 for each group). After HCl aspiration, all animals died at 2–2.5 hours in PAFR-Tg and at 3–3.5 hours in controls, whereas all animals survived in the PAFR-KO group.

Figure 2

Roles of the PAFR gene in acid-induced lung injury. Changes in EL 2 hours after aspiration (n = 8–10). Responses after the administration of HCl (filled bars) or saline (open bars) are shown. ⁺P < 0.05, *P < 0.001 vs. saline-treated groups. ^#P < 0.001 vs. HCl-treated controls.

Figure 3

Roles of the PAFR gene in acid-induced hypoxemia. PaO₂ level 2 hours after aspiration (n = 8–10). Responses after the administration of HCl (filled bars) or saline (open bars) are shown. *P < 0.001 vs. saline-treated groups. ^#P < 0.001 vs. HCl-treated controls.

Figure 4

Roles of the PAFR gene in acid-induced lung edema. The lung W/D 2 hours after aspiration (n = 4–5). Responses after the administration of HCl (filled bars) or saline (open bars) are shown. *P < 0.05 vs. saline-treated groups. ^#P < 0.01 vs. HCl-treated controls.

Figure 5

Roles of the PAFR gene in acid-induced protein leakage. Total protein amounts of BALF 2 hours after aspiration (n = 4–5). Responses after the administration of HCl (filled bars) or saline (open bars) are shown. ⁺P < 0.01, *P < 0.001 vs. saline-treated groups. ^#P < 0.001 vs. HCl-treated controls.

Figure 6

Roles of the PAFR gene in acid-induced neutrophil infiltration. PMN counts of BALF 2 hours after aspiration (n = 4–5). Responses after the administration of HCl (filled bars) or saline (open bars) are shown. *P < 0.001 vs. saline-treated groups.

Figure 7

Photomicrograph of lung tissues from PAFR-Tg (a and b), PAFR-WT (c and d), and PAFR-KO (e and f) mice 2 hours after HCl administration. Hematoxylin-eosin stain. Scale bar in a represents 200 μm in a, c, and e and 50 μm in b, d, and f.