Manipulating Mechanisms of Lung Injury from Bench to Bedside: A Promising Future
By: Mikaeel Valli
Dr. Haibo Zhang, MD, PhD
Scientist, Keenan Research Centre for Biomedical Sciences, St. Michael’s Hospital
Professor, Departments of Anesthesia, Medicine and Physiology, University of Toronto
Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which widespread inflammation in the lungs severely compromises oxygenation capacity, thereby limiting the body’s supply of oxygen. ARDS can be a complication following sepsis, trauma, or pneumonia, among other conditions, and often leads to critical illness and poor prognosis. To combat its high mortality rates, researchers have made promising strides toward improving treatment for ARDS. I had the pleasure of meeting Dr. Haibo Zhang, whose research on ARDS holds promise for management of this acute, life-threatening illness.
In his sunlit office at the Li Ka Shing Knowledge Institute (LKSKI), St. Michael’s Hospital, Dr. Zhang recounts his fellowship in Belgium where he saw promise in treating sepsis patients using specific drugs as part of a clinical trial. Nevertheless, the medications were proven to be ineffective, and the trial failed to produce the anticipated results. “You would think that if you neutralize the toxic infection, you would be cured. But, it’s not quite the case,” Dr. Zhang explains. The unsuccessful trial prompted Dr. Zhang to return to research in search of the cellular origin of ARDS. Subsequently, he decided to pursue his PhD in Critical Care Medicine at Free University of Brussels, which he completed in 1995. In keeping with his original research interest, his lab at LKSKI examines the cellular mechanisms of sepsis and how it causes acute lung injury. In particular, Dr. Zhang’s lab is interested in the mechanisms of innate immunity and infection in the lungs. By understanding ARDS at a cellular level, Dr. Zhang hopes to develop effective treatments for this life-threatening lung injury.
Mechanical ventilation, which assists with or replaces spontaneous breathing, is a critical component in the care of patients with ARDS. Notwithstanding its value in ARDS management, Dr. Zhang explains that mechanical ventilation acts as a double-edge sword—on the one hand, it helps patients breathe, but on the other hand, it can injure the lungs further if not implemented carefully—inducing even more inflammation. From a pharmacological standpoint, there remains a glaring void in the critical care of ARDS patients, as no medications have been proven effective in treating the condition. For this reason, Dr. Zhang has dedicated a portion of his research to the condition most commonly responsible for ARDS in the first place: sepsis. Sepsis occurs when the immune system responds to a bacterial infection but injures the host in the process. That is, certain bacterial infections are associated with the release of an endotoxin known as lipopolysaccharide (LPS), which often leads to a strong inflammatory response that is damaging to the lung tissue. Surprisingly, spending time with his daughter lent Dr. Zhang an ‘aha’ moment about targeting LPS. His daughter pointed out to him that a small worm was crawling on the red skin of her apple. After washing the apple, they cut it in half, and to their surprise found more worms inside. This led Dr. Zhang to speculate that LPS molecules are like the worms in that they are not only seen on the outside of the lung cells, but possibly inside them as well. He put the idea to the test by first placing healthy cells in a petri dish, and then adding tagged LPS molecules. Much like the worms in the apple, Dr. Zhang detected LPS inside the cells, leading him to hypothesize that even upon clearance from the bloodstream, intracellular LPS can still induce an inflammatory response. Since this discovery, Dr. Zhang and his team have identified a key receptor that is responsible for bringing LPS into the cell. They also developed a molecule that can block this receptor from internalizing the LPS, thereby preventing the destructive inflammatory process from damaging the lungs. Dr. Zhang is filing a patent for this molecule, with the hopes that it can provide doctors with an effective way to treat ARDS in the future. “We are hoping to save patients with this molecule,” Dr. Zhang says optimistically.
In addition to their work on preventing the entry of LPS into cells, Dr. Zhang’s team also works to manipulate the effect of host-secreted proteins on the inflammatory response. Specifically, Dr. Zhang studies neutrophils, a type of white blood cell that produces strong, positively charged proteins—called human neutrophil peptides (HNPs)—that kill negatively charged bacteria. In addition to their antimicrobial action, however, this cluster of proteins also activates specific lung cell receptors in the area, triggering inflammatory signaling which consequently damages the lung tissue. Importantly, the team has developed a way to block HNPs from binding to these specific receptors. As a result, HNPs can successfully kill the bacteria without triggering self-destructive inflammation. “This is a new class of antibiotics. This is exciting! Use the endogenous system to fight the infection as opposed to just using the exogenous sources,” says Dr. Zhang enthusiastically. Indeed, the potential of this finding for ARDS patients is far-reaching.
In addition to manipulating the cellular microenvironment in the lungs, the use of stem cells from bone marrow has been of interest for its potential in treating ARDS. Animal models demonstrate that stem cells reduce lung inflammation and thereby the severity of ARDS. In light of these promising results, clinical trials are now under way with hopes for similar findings in humans. As Dr. Zhang explains stem cell treatments, he asks, “When do stem cells become beneficial or detrimental for ARDS patients? It depends on the microenvironment of the lungs.” He highlights the notion of personalized medicine, where one “glove” does not fit all patients. Considering this question, his lab induced mild, moderate and severe lung injury in mice, mimicking the degree of severity seen in patients with ARDS. His team then categorized the mice based on their lung injury severity profile, which was found to affect how they responded to stem cells. “We found that 80% of the profile seen in the mice model can be observed in the patient sample with ARDS. This is so exciting!” Dr. Zhang explains, suggesting that this finding can help clinicians categorize ARDS patients based on their severity profile to predict individual response to stem cell therapy. Furthermore, such profiling will help indicate which patients require a correction of their lung’s microenvironment before receiving stem cell treatment. “This finding is very relevant to guide clinical applications,” Dr. Zhang points out.
The clinical outcomes of Dr. Zhang’s recent findings are still to be determined. “Our main goal is to translate our results into clinical practice. We are trying to take our intellectual property and develop it into pharmaceutical products,” explains Dr. Zhang. He acknowledges that translational research is not easy and requires a lot of patience, as often the process does not go in the desired direction. For this reason, he advises students pursuing research to not get lost in the technical detail and, in the face of obstacles, remember the big picture. For students at the Institute of Medical Science, the big picture involves their project’s contribution to the field of medicine, through advances in diagnosis, patient outcomes, or—in the case of ARDS—lives saved.