4 5 Fibrocytes are mesenchymal progenitors from hematopoietic origin involved in normal and pathologic organ repair. During Background: acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), an ineffective repair is associated with over-mortality. We investigated whether fibrocyte detection in bronchoalveolar lavage fluid (BAL) could be a predictor of outcome during acute lung injury. We prospectively collected BAL from 122 ventilated patients (62-ARDS, 30-ALI, 30-ventilated patients w/o ALI/ARDS). Fibrocytes, Methods: defined as cells expressing CD45 and collagen 1, were quantified by flow cytometry. Chemokines, growth factors and collagen 1 concentrations were measured in BAL supernatants. Ventilated patients were followed up for 28 days after BAL procedure and clinical data recorded. Fibrocytes were detected in 89% of BAL from ventilated patients. The median percentage of BAL fibrocytes was significantly Findings: increased in patients with ALI and ARDS (5.0 %) in comparison with ventilated controls (0.9%, p<0.0001). Fibrocyte percentage correlated with percentage of monocytes/macrophages in BAL (s=0.35, p=0.007). After adjustment for age, comorbidities, administered treatments and severity of illness in a multivariable COX proportional-hazard model, a percentage of BAL fibrocytes over 6% was independently associated with a lower proportion of patients weaned from mechanical ventilation at 28 days (HR (95% CI)= 0,34 (0,15-0,78), p=0,01) and a higher 28-day mortality in ALI/ARDS patients (HR (95% CI)= 6.15 (2.78-13.64), p<0.0001). Fibrocytes are detectable in the alveolar space during ALI/ARDS. BAL Fibrocytes percentage is an independent marker Interpretation: associated with poor survival and requirement for prolonged mechanical ventilation in patients with ALI/ARDS.

Although fibroblasts are key cells in the lung repair/fibrosis process, their characteristics are poorly studied in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The aims of our study were to: 1) determine the biological behaviour of alveolar fibroblasts during ALI; and 2) to evaluate the clinical relevance of positive alveolar fibroblast culture from patients with ALI/ARDS. Cells were cultured from bronchoalveolar lavage (BAL) obtained from 68 critically ill, ventilated patients: ALI n = 17; ARDS n = 31; and ventilated controls n = 20. Patients were followed for 28 days and clinical data was recorded. We studied proliferation, migration and collagen-1 synthesis capacities of fibroblasts. Cells expressing fibroblast markers were cultured from BAL obtained in six (35%) ALI patients and six (19%) ARDS patients, but never from ventilated controls. Alveolar fibroblasts exhibited a persistent activated phenotype with enhanced migratory and collagen-1 production capacities, with hyporesponsiveness to prostaglandin E2 compared to normal lung fibroblasts (p≤0.04). Positive fibroblast culture was associated with both an increased collagen-1 concentration and monocyte/macrophage percentage in BAL fluid (p≤0.01), and with a reduced duration of mechanical ventilation (p<0.001). We conclude that activated alveolar fibroblasts can be cultured either in ALI or ARDS and that their presence might reflect the initiation of the organising phase of ALI.

La migration des fibroblastes pulmonaires humains (FPH) est une étape essentielle du processus de réparation alvéolaire dans les agressions pulmonaires aiguës (Acute Lung Injury, ALI, et Acute Respiratory Distress Syndrome, ARDS). L’objectif de cette étude était de caractériser les médiateurs présents dans le lavage broncho- alvéolaire (LBA) et impliqués dans la migration des FPH dans les ALI/ARDS. La migration de FPH (ATCC CCL-210) a été étudiée dans un modèle de chambre de Boyden modifiée (Transwell® 8,0 μm) en absence et en présence de surnageant de LBA prélevés chez des patients de réanimation, sous ventilation mécanique (VM), suspects de pneumopathie infectieuse. Les Résultats, exprimés en médiane [min-max], étaient comparés par tests non paramétriques. La migration des FPH était stimulée en présence de LBA dans le groupe ARDS (108 % [5-337]) et inhibée dans les autres groupes (témoins ventilés 9 % [3-44] ; ALI 27 % [4-105]), chez les patients prélevés avant le 8e jour de VM (figure). La migration induite par les LBA ayant un effet stimulant était réduite de 53 % [39-79] (n = 5 ; p = 0,03) en présence d’un inhibiteur spécifique des récepteurs au PDGF (AG1296). À l’opposé, les LBA inhibiteurs réduisaient de 48 % [0-97] (n = 8 ; p = 0,01) la migration induite par du rh-PDGF. Cet effet inhibiteur disparaissait après dilution des LBA d’un facteur 4 (51 % [7-128] vs 128 % [45-237] de l’effet stimulant de rh-PDGF) (n = 5 ; p = 0,03), suggérant la présence d’un inhibiteur de PDGF dans les LBA. La migration des FPH, au cours des ALI/ARDS, semble modulée par une balance entre activateur et inhibiteur de la voie du PDGF dans les LBA. Cette balance est en faveur d’une activation de la migration des FPH au cours des lésions alvéolaires les plus sévères.Download : Download full-size image