By virtue of their design as a gas-exchange organ, lungs are constantly exposed to mechanical stimulation associated with inflation-deflation cycles. Pulmonary vascular cells experience four principal mechanical forces: i) shear stress resulting from blood fluid flow and local stresses resulting from blood cells passing through the terminal capillary system; ii) vessel wall strain from intraluminal hydrostatic pressure; iii) cyclic strain caused by heart propulsions; and iv) distension of lung microvasculature caused by respiratory cycles.
These additional mechanical forces form a unique mechanical environment experienced by pulmonary vasculature. The endothelium is located between flowing blood and the vascular wall. Cells lining the arterial circulation are exposed to fluid forces of much greater magnitude than those experienced by other tissues. Endothilial cells (EC) are capable of altering their structure and mechanical properties resulting in the generation of internal cellular stresses that equalize the external forces. In addition to cyclic stretch derived from the intraluminal blood pressure, lung capillary strain is also associated with respiratory cycles.
Normally, mechanical loads on pulmonary vasculature are well tolerated. However, increasing capillary pressure to pathologic levels leads to breaks in the capillary endothelial layer, referred to as “stress failure,” and the development of pulmonary edema. A major pathological condition involving stress failure of pulmonary capillaries leading to increased pulmonary permeability is lung injury induced by excessive mechanical ventilation.
Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS). Pathological lung over-distension caused by mechanical ventilation at high tidal volumes, however, transmits pathologic mechanical stress to alveolar epithelium and pulmonary vasculature, leading to barrier dysfunction. Thus, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury in established ARDS, a syndrome known as ventilator-induced lung injury (VILI).
VILI and ARDS share pathobiologic features such as profound lung inflammatory leukocyte infiltration, cytokine expression, and lung vascular permeability leading to alveolar flooding. Unfortunately, insights into VILI pathobiology have been incremental with no viable therapies realized. We have developed a multi-investigator initiative to take a multi-factorial approach to the study of VILI to increase our understanding of: i) the transcription factors that relay the effects of excessive mechanical stress; ii) the mechanical stress-induced PTMs that influence key signaling pathways involved in VILI responses; iii) the genetic and epigenetic regulation of key target genes involved in VILI responses; and iv) the development of novel therapeutic strategies for VILI utilizing clinically-relevant models to mimic VILI in the setting of ARDS.
Related lines of research include: