By Stefanie Novakowski, PhD Candidate, Kastrup Lab
Upon injury, a healthy adult lung has the robust ability to regenerate and replace damaged cells.1 Despite this healing capacity, respiratory disease remains a leading cause of death worldwide; therefore, understanding the molecular processes that control lung repair is an important research goal in uncovering new therapies. Lung repair is a complex process that involves activation of progenitor cells, populations of cells which differentiate into mature cells with more specialized functions. Examples of mature cells include the epithelial cells that line the inside of the lung and the endothelial cells that line blood vessels.2,3 The repair process also involves the recruitment of immune cells to the site of damage and formation of collagen fibers around the injured cells to help facilitate repair. Dysfunction in any of these steps can lead to a thickening and remodeling of the cell walls that form the lung’s aveoli, the tiny air sacs where gas exchange occurs. These changes cause loss of organ function and ultimately death.
Members of the McNagny lab at the Centre for Blood Research focus their efforts on understanding CD34, a cell surface protein typically used as a marker for progenitors of blood cells.4 CD34 has also been identified in other progenitor cell subsets, including those involved in lung injury, yet its function in these populations has not been well defined. In this paper, Bernard Lo of the McNagny lab, and collaborators, investigated the role of CD34 in lung disease using mouse models of acute lung injury and influenza-induced lung injury. Chronic inflammation is a hallmark of dysregulated lung repair, and due to the known role of CD34 in promoting migration of immune cells towards sites of injury, it was hypothesized that mice missing the CD34 gene (Cd34-/-) would be protected from this dysfunction. Surprisingly, this was not the case. Lo et al. demonstrated that Cd34 -/- mice had increased mortality compared to wildtype mice, yet no difference in the amount of acute lung inflammation was observed between populations. Rather, in Cd34 -/- mice, the interaction between the endothelial cell layer formed by the blood vessels surrounding the aveoli and the epithelial layer forming the aveoli was disrupted. This caused leakage of excess fluid into this space, impairing gas exchange and leading to death.5 Analysis of the lungs in injured mice led to the discovery that this disruption was due to poor attachment of the blood vessels to the extracellular matrix (ECM), a network of proteins lying between the aveoli and blood vessels, while the interaction between the ECM and aveoli remained intact.
This research demonstrates a new protective role of CD34 in maintaining the structural integrity of the alveolar wall during lung injury. These results were unexpected, as it has previously been shown that CD34 act as an antiadhesive in other cell types. Lo et al. speculate that during lung repair CD34 may be promoting adhesion by facilitating proper activation of integrins, proteins that interact with the ECM, rather than through a direct interaction of CD34 with the ECM. To test this hypothesis, they propose future structural and functional analyses that may answer this question. Ultimately, this work provides a new link between vascular defects and respiratory disease, and may provide insights for the development of better treatments for respiratory disease.