Lung Repair and Regeneration in ARDS: Role of PECAM1 and Wnt Signaling

Abstract

ARDS is an acute inflammatory pulmonary process triggered by severe pulmonary and systemic insults to the alveolar-capillary membrane. This causes increased vascular permeability and the development of interstitial and alveolar protein-rich edema, leading to acute hypoxemic respiratory failure. Supportive treatment includes the use of lung-protective ventilatory strategies that decrease the work of breathing, can improve oxygenation, and minimize ventilator-induced lung injury. Despite substantial advances in supportive measures, there are no specific pharmacologic treatments for ARDS, and the overall hospital mortality rate remains about 40% in most series. The pathophysiology of ARDS involves interactions among multiple mechanisms, including immune cell infiltration, cytokine storm, alveolar-capillary barrier disruption, cell apoptosis, and the development of fibrosis. Here we review some new developments in the molecular basis of lung injury, with a focus on possible novel pharmacologic interventions aimed at improving the outcomes of patients with ARDS. Our focus is on platelet-endothelial cell adhesion molecule-1, which contributes to the maintenance and restoration of vascular integrity following barrier disruption. We also highlight the wingless-related integration site signaling pathway, which appears to be a central mechanism for lung healing as well as for fibrotic development.

Keywords: endothelial injury; mechanical ventilation; platelet-endothelial cell adhesion molecule; pulmonary fibrosis; ventilator-induced lung injury; wingless-related integration site.

Figure 1

Proposed platelet-endothelial cell adhesion molecule-1 (PECAM1) and Src signaling pathway activation in ARDS and in ventilator-induced lung injury. The combined effects of inflammatory mediators and repetitive opening and closing of alveoli during mechanical ventilation inflict shear stress on the endothelial cells of the pulmonary capillary blood vessels. The resultant mechanical force is transmitted through cytoskeletal elements to sites of cell-to-cell adhesion, where a transmembrane protein, known as PECAM1, responds by activating downstream signaling pathways, including those involving Src and signal transducer and activator of transcription-3 (STAT-3). The STAT-3 transcription factor may play a role in initiating the inflammatory response seen in ventilator-induced lung injury.

Figure 2

Proposed molecular Wnt signaling pathway in lung fibrosis during ARDS. Wnt signaling begins when a Wnt protein binds to a Frizzled family receptor. To facilitate Wnt signaling, coreceptors such as lipoprotein receptor-related protein (LRP) and others may be required. On activation of the receptor, Axin is removed from the receptor complex and activates β-catenin. β-Catenin moves into the nucleus, binds to a transcription factor on DNA, and activates transcription of target genes. Wnt = wingless-related integration site.

Figure 3

Schematic depicting proposed pathway for the generation of proximal or distal epithelial lineages in the lung on activation of human induced pluripotent stem cell (iPSC)-derived airway epithelium via Wnt signaling.