In the average person’s lifetime, they will take over 600 million breaths, which will stretch the tissues of the lungs as they inhale, and relax the tissues as they exhale. Simple and involuntary breathing are vital functions that the lungs perform to not only stay alive, but help maintain tissue health as well.
Recently, researchers from the Wyss Institute at Harvard University have just revealed that there is new evidence that the constant pattern of stretching and relaxing actually has much more importance attached to it, it actually produces the body’s immune response against intrusive viruses, just like COVID-19.
The research team used a ‘Human Lung Chip’ meant to replicate the functions and structures of a lung air sac, otherwise known as the “alveolus,” where they figured out that ‘by applying mechanical forces that mimic breathing motions, they could suppress influenza virus replication, while activating innate protective immune responses.’
According to co-first author, Haiqing Bai, Ph.D., a Wyss Technology Development Fellow at the Institute, “This research demonstrates the importance of breathing motions for human lung function, including immune responses to infection, and shows that our Human Alveolus Chip can be used to model these responses in the deep portions of the lung, where infections are often more severe and lead to hospitalization and death.”
The study findings were published in the Nature Communications journal.
Generating a ‘Flu-On-A-Chip’
During the early phases of the COVID-19 pandemic, it was obvious that the most vulnerable organ in the body were the lungs. That’s because as a response to the infection, when inflammation in the lungs could cause a “cytokine storm” that had fatal consequences in the worst of cases. But since the lungs are considered a highly complex organ, it was also difficult to exactly replicate them and their unique functions and features within the lab. Because of this complexity, it also lessened science’s understanding of the way the lungs function at the tissue and cell levels, in both healthy and unhealthy states.
The reason for creating the Wyss Institute’s Human Organ Chips program was precisely to address this issue, which has since been able to replicate the functions of a number of different human organs within the lab, such as the lung. Some of the projects have been funded by DARPA and the NIH since 2017, where the Wyss researchers have been busy attempting to replicate a variety of diseases just like the Lung Airway and Alveolus Chips in order to observe just how lung tissues react to such viruses with the ability of pandemic proportions, as well as to test possible treatments.
As per Dr. Bai, during his Ph.D. training, he studied diseases ‘that affect the tiny air sacs deep inside the lungs where oxygen is rapidly exchanged for carbon dioxide.’ He explained that this was the foundation that helped him prepare to handle the challenges of recreating a flu infection in an Alveolus Chip in order for the team to study how ‘these deep lung spaces mount immune responses against viral invaders.’
To recreate the interface between human air sacs and their blood-transporting capillaries, Bai and his team ‘lined the two parallel microfluidic channels of an Organ Chip with different types of living cells – alveolar lung cells in the upper channel and lung blood vessel cells in the lower channel.’ Then to copy the conditions that alveoli live in, in the human lung, ‘the channel lined by alveolar cells was filled with air while the blood channel was perfused with a flowing culture medium containing nutrients that are normally delivered via the blood.’ The channels were also separated by a porous membrane which allowed the molecules to flow in between them.
The researchers also shared that in previous studies done in the Wyss Institute, they were able to establish that by applying cyclical stretching to the Alveolus Chips in order to imitate the usual breathing motions managed to produce biological responses that mimic those seen in vivo. They accomplished this by applying suction to hollow side chambers that are adjacent to the cell-lined fluidic channels which then rhythmically stretched and relaxed the lung tissues by 5%, which is basically the same as how human lungs tend to experience with each breath.
Then the team infected these “breathing” Alveolus Chips with H3N2 influenza by introducing the virus into the air channel, where they observed the development of many known markers of the influenza infection, such as ‘the breakdown of junctions between cells, a 25% increase in cell death, and the initiation of cellular repair programs.’ The infection also increased levels of multiple inflammatory cytokines in the blood vessel channel, which included type III interferon, which is explained as ‘a natural defense against viral infection that is also activated in in vivo flu infection studies.’
Moreover, the research also found that ‘the blood vessel cells of infected chips expressed higher levels of adhesion molecules, which allowed immune cells including B cells, T cells, and monocytes in the perfusion medium to attach to the blood vessel walls to help combat the infection.’ These results established that the Alveolus Chip was indeed creating an immune response against H3N2 that echoed what would happen in the lungs of a human patient that was infected with the flu virus.
The Importance of Focusing On Your Breath
The team then did the exact same experiment, except they did it without the mechanical breathing motions. Much to their surprise, the chips exposed to breathing motions had ‘50% less viral mRNA in their alveolar channels and a significant reduction in inflammatory cytokine levels compared to static chips.’ Through genetic analysis they found that the mechanical strain had indeed activated molecular pathways that are related to immune defense and multiple antiviral genes, while the activations were reverse after they cyclical stretching was put to a halt.
Former Wyss Technology Development Fellow and co-first author Longlong Si, Ph.D., who is currently a professor at the Shenzhen institute of Advanced Technology in China, said, “This was our most unexpected finding – that mechanical stresses alone can generate an innate immune response in the lung.”
Considering that there are times the lungs may experience strains that are higher than 5%, like with chronic obstructive pulmonary disorder (COPD) or when they are put on mechanical ventilators, scientists chose to increase the strain to 10% to see what the response would be. As a result, the ‘higher strain caused an increase in innate immune response genes and processes, including several inflammatory cytokines.’
Profesor Si shared, “Because the higher strain level resulted in greater cytokine production, it might explain why patients with lung conditions like COPD suffer from chronic inflammation, and why patients who are put on high-volume ventilators sometimes experience ventilator-induced lung injury.”
The research group even went a step further by comparing the RNA molecules that were present in the cells within strained vs. static Alveolus Chips in order to see if they could figure out how the breathing motions were creating an immune response. They identified a ‘calcium-binding protein, called S100A7, that was not detected in static chips but highly expressed in strained chips, suggesting that its production was induced by mechanical stretching. They also found that increased expression of S100A7 upregulated many other genes involved in the innate-immune response, including multiple inflammatory cytokines.’
Due to the encouraging result, the research group took the virus H3N2 and infected the strained Alveolus Chips. Then two hours after infection, they administered the azerliragon drug at its therapeutic dose.
The medication managed to substantially block the production of the inflammatory cytokines, which was further enhanced after adding the antiviral drug molnupiravir, which has been approved for the use of COVID-19 patients, to the treatment regimen.
At the same time, although azeliragon happens to be a promising anti-inflammatory drug, scientists have warned that more studies are required to figure out a safe and effective treatment for humans. In the end, hearty breathing is still something that people can do throughout any season in their lives to promote their health.
Recommended For You
