Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury.

FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

Keratinocyte growth factor-2 is protective in lipopolysaccharide-induced acute lung injury in rats.

Keratinocyte growth factor-2 (KGF-2) plays a key role in lung development, but its role in acute lung injury has not been well characterized. Lipopolysaccharide instillation caused acute lung injury, which significantly elevated lung wet-to-dry weight ratio, protein and neutrophils in bronchoalveolar lavage fluid (BALF), inhibited surfactant protein A and C expression in lung tissue, and increased pathological injury. Pretreatment with KGF-2 improved the above lung injury parameters, partially restored surfactant protein A and C expression, and KGF-2 given 2-3 days before LPS challenge showed maximum lung injury improvement. Pretreatment with KGF-2 also markedly reduced the levels of TNF-α, MIP-2, IL-1ß and IL-6 in BALF and the levels of IL-1ß and IL-6 in lung tissue. Histological analysis showed there was increased proliferation of alveolar type II epithelial cells in lung parenchyma, which reached maximal 2 days after KGF-2 instillation. Intratracheal administration of KGF-2 attenuates lung injury induced by LPS, suggesting KGF-2 may be potent in the intervention of acute lung injury.

Increased claudin-3, -4 and -18 levels in bronchoalveolar lavage fluid reflect severity of acute lung injury.

BACKGROUND AND OBJECTIVE: Acute lung injury (ALI) is characterized by disruption of lung epithelial and endothelial cells, leading to increased membrane permeability and loss of barrier function. Claudins are key components of tight junctions (TJ) that regulate paracellular permeability, and play an important role in alveolar epithelial barrier function and fluid clearance. However, whether claudin-3, -4, -18 or -5 expression changes in Pseudomonas aeruginosa (PA)-induced ALI and the clinical significance of such change is unknown. METHODS: Rats underwent intratracheal instillation of PA, and samples were collected prior to and 3, 9 and 24 h after instillation. Lung injury was evaluated by bronchoalveolar lavage fluid (BALF) total protein, arterial blood gas analysis, lung injury score, and expression of surfactant protein and von Willebrand factor. Claudin expression in lung was measured with quantitative real-time polymerase chain reaction and western blotting, and in BALF by enzyme-linked immunosorbent assay. The relationship between claudins in BALF and lung injury grade were analysed with Spearman's rank correlation. Alveolar epithelium, endothelium and TJ ultrastructure were observed with electron microscopy. RESULTS: Claudin-4, -18 and -5 mRNA levels increased significantly 24 h after PA instillation in the most severe lung injury cases, whereas there was no significant change in protein levels. Claudin-3, -4 and -18 levels in BALF increased most 24 h after PA instillation; this paralleled alveolar epithelial disruption and lung injury severity. CONCLUSIONS: Claudin-3, -4 and -18 released into the alveolar compartment is highly associated with barrier function loss caused by alveolar epithelial injury.