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Regulation of hepatocyte growth factor secretion by fibroblasts in patients with acute lung injury

¹Institut National de la Santé et de la Recherche Médicale Unité 700, Faculté Xavier Bichat, Paris; ²Service de Pneumologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris; ³Département d'Anesthésie-Réanimation, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris; ⁴Service d'Anesthésie et de Réanimation Chirurgicale, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris; and ⁵Laboratoire de Biochimie A, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France

Submitted 12 March 2007 ; accepted in final form 4 December 2007

The mechanisms of pulmonary repair in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are poorly known. Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are key factors involved in alveolar epithelial repair, present in the bronchoalveolar lavage fluid (BALF) from patients with ALI/ARDS. The role of BALF mediators in their production remains to be determined. We evaluated the overall effect of BALF from 52 patients (27 ventilated patients with ALI/ARDS, 10 ventilated patients without ALI, and 15 nonventilated control patients) on HGF and KGF synthesis by lung fibroblasts. Fibroblasts were cultured in the presence of BALF. HGF and KGF protein secretion was measured using ELISA, and mRNA expression was evaluated using quantitative real-time RT-PCR. Only BALF from ALI/ARDS patients upregulated both HGF and KGF mRNA expression and protein synthesis (+271 and +146% for HGF and KGF, respectively). BALF-induced HGF synthesis from ALI/ARDS patients was higher than that from ventilated patients without ALI (P < 0.05). HGF secretion was correlated with BALF IL-1β levels (rho = 0.62, P < 0.001) and BALF IL-1β/IL-1 receptor antagonist ratio (rho = 0.54, P < 0.007) in the ALI/ARDS group. An anti-IL-1β antibody partially (>50%) inhibited the BALF-induced HGF and PGE₂ secretion, whereas NS-398, a specific cyclooxygenase-2 (COX-2) inhibitor, completely inhibited it. Anti-IL-1β antibodies as well as NS-398 reversed the COX-2 upregulation induced by BALF. Therefore, IL-1β is a main BALF mediator involved in HGF secretion, which is mediated through a PGE₂/COX-2-dependent mechanism. BALF mediators may participate in vivo in the production of HGF and KGF by lung fibroblasts during ALI/ARDS.

keratinocyte growth factor; acute respiratory distress syndrome; bronchoalveolar lavage fluid; interleukin-1β; cyclooxygenase-2; prostaglandin E₂

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