A paper published in the journal Nature Communications, in which IBioBA’s Max Planck Guest Laboratory participated, described a molecular mechanism by which lung tissue repair is induced after damage caused by respiratory infection. The finding could lay the groundwork for the development of drugs to treat acute viral lung infections.

Influenza is an acute respiratory disease caused by the Influenza virus that generally produces a mild and self-limiting illness, although in certain vulnerable population groups there is an increased risk of developing severe disease and complications associated with the infection.

The Heart and Lung Guest Laboratory of the Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA, CONICET-Max Planck Partner Institute) works closely with the Max Planck Institute for Heart and Lung Research in Bad Nauheim and the University Hospital Giessen in Germany. One of his lines of research is focused on elucidating the cellular signals that promote lung tissue regeneration. Manipulating these signals could potentially prevent the deterioration of lung function due to ageing and severe respiratory infections caused by viruses such as influenza or COVID-19.

It is in this line of research that a paper recently published in the journal Nature Communications describes how immune system cells called “macrophages” promote the regeneration of lung tissue after damage caused by acute influenza virus infection. This tissue repair process involves the Plet1 protein.

The cycle of a viral infection

The whole process of an infection has two distinct stages: first there is an inflammatory surge aimed at fighting the infection, and then, from day 8 onwards, the stage of resolution of the inflammation and recovery of the damaged tissue begins, which can last up to a month. When the infection begins to subside, the lung tissue sends out signals asking for assistance in resolving the inflammatory process and macrophages come calling. These cells are a type of white blood cell and one of their main functions is to keep the tissue in homeostasis, i.e. in optimal conditions for its functioning.

“The infectious process induces inflammation in the lung tissue, and the repair of the damaged tissue depends on the correct resolution of the inflammatory process. This is the whole cycle, and macrophages are involved in all phases”, explains Maximiliano Ferrero, researcher at the Max Planck Guest Laboratory.

 

The role of macrophages

“It has long been known that macrophages control the immune response, and it has also been known that lung macrophages play important roles in maintaining tissue under homeostatic conditions. Less recently, it has also been understood that macrophages are actively involved in the cessation of inflammation (resolution), and the regeneration of damaged tissue, actively promoting the return to homeostasis”, says Ferrero, first author of the paper together with two scientists from the German institutions.

Macrophages receive specific signals from the environment indicating that the damage is over and the tissue needs to be repaired. The research team saw that in response to these signals, macrophages produce Plet1: a protein that triggers the proliferation of lung progenitor cells, i.e. activates tissue regeneration.

“What we show in the publication is that Plet1 plays a key role in tissue re-epithelialization. We describe a previously unknown mechanism by which macrophages signal lung alveolar progenitor cells to proliferate and then differentiate into the type of cell that performs gas exchange, fully restoring lung function”, says Ferrero.

In the future, this discovery has the potential to lay the groundwork for the development of drugs to protect the lungs from acute viral lung infections, both influenza and other respiratory viruses, especially in people who are less able to resolve infection or inflammation, such as the elderly. “What we hope is that by studying the mechanisms that lead to lung tissue regeneration, we can manipulate them so that in situations where that mechanism fails or is depressed, we can make it faster or more efficient. This can happen when we have described all the steps of this mechanism and the different conditions under which it is activated”, the researcher adds.

One leg in Argentina and one leg in Germany

The publication took about 10 years of work, involved multiple researchers and involved different types of experiments. Many tests were carried out at IBioBA, together with Melina Cohen, a laboratory technician, and Balachandar Selvakumar, who worked for five years in the guest laboratory. Regarding the collaborative work between Argentina and Germany performed by the Max Planck Guest Laboratory at IBioBA-CONICET-MP, Maximiliano Ferrero says that “it is important to carry out this type of activity because it not only connects you with sources of funding and technologies, but also enriches the research. When people from different places and experiences get involved, what you end up with is a much better quality of work”.