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The surprising link between macrophages and lung disease

Dr. Patrick Hume shares his mission to investigate the influence of cigarette smoke on the role of lung macrophages and reveals how his findings could help improve future therapies.

Dr. Patrick Hume, pulmonologist and physician-researcher at National Jewish Health

Smoking is one of the leading causes of preventable death worldwide. According to the World Health Organization, tobacco kills more than 8 million people a year, making the global tobacco epidemic one of the greatest public health challenges we face. In this exclusive interview, we speak with Dr. Patrick Hume, pulmonologist and physician-researcher at National Jewish Health, to learn more about his pioneering research on the link between lung disease and lung macrophages. Hume and his team of experts are on a mission to combat this public health crisis by gaining a better understanding of the role of macrophages in different locations in the lungs, as well as how they dictate how our lungs respond to different noxious stimuli, including exposure to cigarette smoke. Hume also explains how Olympus microscope technology helps him achieve his research goals and describes his goals of expanding our understanding of lung disease to save lives.

Smoking and respiratory diseases

Macrophages are effector cells of the innate immune system and play a central role in maintaining tissue homeostasis, eliminating damaged cells, and secreting pro-inflammatory and antimicrobial mediators. “We want to understand how the body responds to cigarette smoke, specifically how the airways in the lungs are affected by cigarette smoke,” Hume says. Thanks to medical advances and healthier living, it is now common knowledge that repeated exposure to cigarette smoke can cause direct damage and scarring to the lungs, alveolar spaces and airways. This damage can eventually lead to chronic obstructive pulmonary disease (COPD), emphysema, and many other chronic, incurable conditions.

Hume and his team believe that macrophages are important cells for initiating the immune response that occurs after exposure to cigarette smoke and want to better understand the role of macrophages in the lungs. To improve this understanding, Hume’s team is focusing on the role that macrophages play at very specific lung locations.

“Certain macrophages, including alveolar macrophages found in the alveoli, are present in the airspaces and are responsible for clearing particles and promoting lung healing. However, there are also populations of macrophages that exist in the layers tissues of the lungs, such as inside the walls of the airways and between the alveolar spaces,” says Hume. “We are interested in understanding how the location of these particular cells dictates their unique function.”

Interestingly, the number of macrophages present in the lungs of a smoker is significantly higher than that of a non-smoker. “We suspect that these macrophages play an important role in guiding the immune response, and repeated injury and activation of these macrophages may ultimately result in aberrant scarring that amplifies the response,” Hume hypothesizes. “I believe too many of these macrophages are a bad thing, but that’s still uncertain.” Hume and the team are now trying to understand where these cells are found in the lungs and how their location affects surface expression and genomic transcription.

Help end the tobacco epidemic

Smoking has long been linked to the cause and development of many respiratory diseases, but there are still many unanswered questions and challenges to overcome, especially for the National Jewish Health team. “One of our hurdles is being able to locate good tissue samples and good microscopy techniques to help us better understand the location of macrophages. What we want to be able to do is link microscopy to sequencing and to functional testing,” says Hume. Combining microscopy with sequencing and functional testing will help them understand the roles that macrophages play at different locations and whether there are multiple subsets of macrophages at those locations that all play different roles. Hume adds, “Ultimately the reason we’d like to do this is to understand the impact macrophages have on disease promotion and prevention.” limit the response and damage caused by cigarette smoke, the team would like to increase the activity of macrophages.However, if they find that macrophages are harmful and lead to ci aberrant catrization, they should rather limit them. “This can be used to guide future therapies and prevent the onset of disease,” he says.

Another major hurdle the team often faces is the ability to study macrophages located in many different organs. “For years, researchers have used techniques like lung digestion, where you take a piece of lung from a human or a mouse and expose it to various enzymes to break down collagen and other connective tissues. “, explains Hume. “Sometimes we also use mechanical digestion to try to remove individual cells from the tissue, which is very useful for performing techniques, such as flow cytometry, to understand the cellular composition of the lung.” Unfortunately, a problem associated with this process is that cell location information can be lost in the digestion process. “A key challenge in the field has been how to identify and study these cells, without disrupting their localization? That’s why we really focused on using advanced microscopy techniques and quantitative microscopy techniques, like stereology or morphometrics, to understand where these cells are,” Hume continues. “We also used techniques such as fluorescence microscopy and targeted antibody labeling to understand the expression, transcription, and hopefully function of these cells in their specific locations without disruption.”

New hope for patients

Microscopy has certainly pushed the boundaries of scientific discovery, allowing us to observe the microscopic world like never before. Despite such success, interpreting microscopic images can be a challenge. “What has long hampered microscopy-based research techniques is that anyone can take a close-up image of a specific part of the tissue and look at the cells, and they could easily come to a conclusion about the where these cells are and what these cells are doing,” says Hume. “So, a lot of caution has to be exercised when interpreting single microscopic images.”

To help overcome these obstacles, Hume uses Olympus’ SLIDEVIEW™ VS200 research slide scanner to capture high-quality virtual slide images. “A key advantage of the VS200 is that it is a very fast, reliable and high throughput whole slide scanner,” he shares. “We’ve come to rely on our ability to do four- or five-channel fluorescent antibody staining, and now we can do high-throughput imaging of the whole slide to get a view of what’s going on. in all the different parts of the lung.” This technology helps Hume and his team understand where cells are on a single slide, whether around vessels or airways. “This microscope has very high throughput, so now we have the ability to scan hundreds of slides at once with a single setup,” Hume says. “It can really help us get a broader picture of the overall structure of the lung.”

The research group combines this technology with advanced microscopy techniques, including stereology, to ensure unbiased methods interpret cell number and size. “Although stereology alone has been around for a while, a major limitation is that it is labor intensive and requires a user to take images individually and quantify them,” he shares. “The main advantage of this technology is its ease of use. This technology has been designed in such a way that hardware and software work very well together, which creates a simple user interface and user experience. Hume also points to the quality of the optics and cameras as another notable advantage. He explains, “We can take really good clear pictures and we’ve been really impressed with the results we’re getting.

Future prospects

Looking ahead, Hume and his team of expert researchers are on a mission to better understand the role of lung macrophages and how this research could be used to help better develop future therapies. “We hope to improve human life and reduce the burden of chronic disease, including chronic obstructive pulmonary disease and emphysema,” Hume says. “What we really want to do is understand how cells in the lungs change in response to exposure to cigarette smoke and what role these macrophages play.” Hume hopes that he will soon be able to identify important cell subtypes that could be targeted by future therapies, either to promote beneficial cells or to limit the effects of deleterious cells.