Alveolar fluid in acute respiratory distress syndrome promotes fibroblast migration: role of platelet-derived growth factor pathway*.
OBJECTIVE
Fibroblast migration is an initiating step in fibroproliferation; its involvement during acute lung injury and acute respiratory distress syndrome remains poorly understood. The aims of this study were: 1) to determine whether bronchoalveolar lavage fluids from patients with acute lung injury/acute respiratory distress syndrome modulate lung fibroblast migration; 2) to assess lung fibroblast migration's clinical relevance; and 3) to evaluate the role of the platelet-derived growth factor pathway in this effect.


METHODS
Prospective cohort study.


METHODS
Three intensive care units of a large tertiary referral center.


METHODS
Ninety-three ventilated patients requiring bronchoalveolar lavage fluids were enrolled (48 with acute respiratory distress syndrome, 33 with acute lung injury, and 12 ventilated patients without acute lung injury/acute respiratory distress syndrome).


METHODS
After bronchoalveolar lavage fluids collection during standard care, the patients were followed up for 28 days and clinical outcomes were recorded. Migration assays were performed by using a Transwell model; bronchoalveolar lavage fluids platelet-derived growth factor and soluble platelet-derived growth factor receptor-α were characterized by Western blot and measured by ELISA.


RESULTS
Most of the bronchoalveolar lavage fluids inhibited basal fibroblast migration. Bronchoalveolar lavage fluids chemotactic index increased with severity of lung injury (28% in patients without acute lung injury/acute respiratory distress syndrome and with acute lung injury vs. 91% in acute respiratory distress syndrome patients; p = .016). In acute lung injury/acute respiratory distress syndrome patients, inhibition of basal fibroblast migration by bronchoalveolar lavage fluids below 52% was independently associated with a lower 28-day mortality (odds ratio [95% confidence interval] 0.313 [0.10-0.98], p = .046). Platelet-derived growth factor-related peptides and soluble platelet-derived growth factor-Rα were detected in all bronchoalveolar lavage fluids from acute lung injury/acute respiratory distress syndrome patients. The effect of bronchoalveolar lavage fluids stimulating migration was inhibited by a specific platelet-derived growth factor receptor inhibitor (AG1296). Bronchoalveolar lavage fluids inhibiting migration reversed the effect of rh-platelet-derived growth factor-BB and reduced by 40% the binding of 125I-platelet-derived growth factor-BB to fibroblast cell surface in favor of a role for platelet-derived growth factor-sRα.


CONCLUSIONS
: Together, our results suggest that during acute lung injury, fibroblast migration is modulated by bronchoalveolar lavage fluids through a platelet-derived growth factor/platelet-derived growth factor-sRα balance. Migration is associated with clinical severity and patient 28-day mortality.
Inserm, Unité 700, Université Paris 7 Denis Diderot, Paris, France. pascale.piednoir@bch.aphp.fr
Pascale
P
Piednoir
Christophe
C
Quesnel
Laurent
L
Nardelli
Véronique
V
Leçon
Lila
L
Bouadma
Sigismond
S
Lasocki
Ivan
I
Philip
Arnaud
A
Mailleux
Paul
P
Soler
Bruno
B
Crestani
Monique
M
Dehoux
D055371:Acute Lung Injury / Q000453:epidemiology / Q000378:metabolism*; D000368:Aged; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007362:Intensive Care Units; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000401:mortality; D015999:Multivariate Analysis; D009504:Neutrophils / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011446:Prospective Studies; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000453:epidemiology / Q000378:metabolism*; D012720:Severity of Illness Index; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016209:Interleukin-8; D010982:Platelet-Derived Growth Factor; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; D017479:Receptors, Platelet-Derived Growth Factor