Effects of mesenchymal stromal cell (MSC) carrying Hepatocyte Growth factor (HGF) in a mouse model of Acute Respiratory Distress Syndrome (ARDS) associated lung fibrosis
CCCF ePoster library. Islam D. Oct 27, 2015; 117358; P70
Diana Islam
Diana Islam
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Introduction: ARDS is a complex disorder with high mortality among critically ill patients, and most non-survivors suffer complications of pulmonary fibrosis. MSC delivery in preclinical models of ARDS has demonstrated significant improvements in lung function and recovery from acute injury, however its role in fibrosis remains unclear. In a mouse model of ARDS induced by mechanical ventilation (MV), we found that MSC delivery can protect the lung from MV-induced lung injury when the lung proteomic analysis showed no pro-fibrotic profiles. However, in a two-hit model of ARDS after hydrochloric acid (HCl) instillation and MV, MSC delivery further aggravated both inflammation and fibrosis when the lung proteomic profiles showed increased pro-inflammatory and pro-fibrotic factors. To improve the therapeutic efficacy of MSC we transduced MSC with the gene of the anti-inflammatory cytokine Interleukin-10 (IL-10) or/and the anti-fibrotic growth factor HGF using lentivirus (LV).

Hypothesis: Delivery of MSC carrying IL-10 or/and HGF gene will attenuate the lung fibrotic development during ARDS.
Method: LV engineered carrying human genes of IL-10, HGF or Luciferase (control) were developed and transduced in MSC, the MSC phenotype remained unchanged following the gene transductions. The time course of overexpression of IL-10 and HGF by MSC was confirmed both in-vitro and in-vivo conditions. 2 days after HCl induced ARDS either 1)Vehicle (PBS) 2)MSC 3)MSC+Luiferase 4)MSC+IL-10 5)MSC+HGF 6)MSC+IL-10/MSC+HGF (50% mixture of IL-10 and HGF transduced MSC) were delivered via intra-tracheal and intra-venous routes (0.5x106 cells each route). 7 days after injury lung fibrosis was accessed using histology and Fibronectin (FN) and Fibrinogen (Fbg) levels in bronchioalveolar lavage fluid (BALF). Inflammation was accessed by differential cell count of BALF and cytokine profiling.
Results: All of the 3 types of LVs successfully transduced MSC without changing their phenotype. IL-10 and HGF production in-vitro was stable, in-vivo elevated levels of IL-10 and HGF was detected in lung tissue upto 7 days. After HCl injury MSC+IL-10 and MSC+HGF reduced cell infiltration into alveolar space compared to MSC alone. The fibrotic markers fibrinogen and fibronectin levels significantly reduced after MSC+HGF and MSC+IL-10/MSC+HGF combination therapy compared to MSC alone. However MSC+IL-10 did not reduce fibrotic marker levels.
Conclusion: MSC mediated overexpression of HGF during the inflammatory phase of ARDS may accelerate the repair process by supressing both inflammation and pulmonary fibrosis. This approach may be incorporated in ARDS clinical trials using MSC to maximize its therapeutic potential.
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