Although patients with ARDS must be mechanically ventilated for survival, it is well established that the mechanical forces generated by the ventilator can exacerbate lung injury and inflammation. In addition to identifying the biomechanical mechanism responsible for physical damage to the lung (see above), my research group has recently used in-vitro, ex-vivo and in-vivo techniques to investigate how the abnormal forces associated with the ventilator influence pro-inflammatory signaling. We have specifically developed a set of in-vitro, ex-vivo and in-vivo models of mechanically induced lung inflammation and have demonstrated that mechanical forces activate innate immunity pathways (TLR4) and strongly stimulate the production of pro-inflammatory cytokines from small airway epithelia. We have also identified several microRNAs, including miR-146a, which can regulate this mechanically-induced inflammation. Specifically, we have demonstrated that miR-146a is upregulated during mechanical ventilation in human subjects but that this upregulation is not sufficient to mitigate the inflammatory responses that occur during ventilation. Therefore, we have developed novel nanoparticle based gene delivery systems to therapeutically over-express this microRNA and have demonstrated that this nanomedicine approach can effectively downregulate lung inflammation during mechanical ventilation. We are currently using computational and machine-learning tools to identify the optimal delivery strategies to use in human subjects with heterogenous lung injury and fluid occlusion.
Selected Publications:
Higuita-Castro N., Shukla, V.C., Mihai, C., Ghadiali, S.N., Simvastatin Treatment Modulates Mechanically-Induced Injury and Inflammation in Respiratory Epithelial Cells, Annals of Biomedical Engineering, 2016, DOI: 10.1007/s10439-016-1693-4.
Nelson K, Bobba, C, Eren E, Spata T, Tadres, M, Hayes Jr, D., Black SM, Ghadiali S*, Whitson, BA*. Method of isolated ex-vivo lung perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program, Journal of Visualized Experiments, (96), e52309, 2015,*equal contributions
Huang, Y., Crawford, M., Higuita-Castro, N., *Nana-Sinkam, P., *Ghadiali, S.N., MiR-146a Regulates Mechanotransduction and Pressure-Induced Inflammation in Small Airway Epithelium, FASEB Journal, 26:3351-3364, 2012. *equal contributions
Huang, Y., Haas, C., Ghadiali, S.N., Influence of Transmural Pressure and Cytoskeletal Structure on NF-κB Activation in Respiratory Epithelial Cells, Cellular and Molecular Bioengineering, 3(4): 415-427, 2010.