A new study headed by researchers at the University of Malta claims to be the first to investigate gene expression changes in scuba divers with decompression sickness (DCS), a potentially deadly condition that is also known as “the bends.” The study results point to the upregulation of genes involved in inflammation and white blood cell activity in DCS, and could lead to the identification of biomarkers that will help doctors to diagnose the condition more precisely.
“We showed that decompression sickness activates genes involved in white blood cell activity, inflammation, and the generation of inflammatory proteins called cytokines,” explained Nikolai Pace, PhD, who is the corresponding author of the team’s published paper in Frontiers in Physiology. “Basically, decompression sickness activates some of the most primitive body defense mechanisms that are carried out by certain white blood cells.” Pace and colleagues described their findings in a report titled, “Acute effects on the human peripheral blood transcriptome of decompression sickness secondary to scuba diving.”
Decompression sickness is a potentially lethal condition that can affect divers. Symptoms include joint pain, a skin rash, and visual disturbances, and in some individuals, the condition can be so severe that it leads to paralysis and death. Researchers have known about “the bends” for more than 100 years—a paper published in 1908 correctly hypothesized the involvement of gas bubbles forming in blood and tissue because of a decrease in pressure—but we still understand relatively little about its physiological basis. Animal studies have suggested that inflammatory processes may have a role in decompression sickness, but no one had previously studied this in humans.
Divers have developed methods, such as controlled ascents, to reduce the risk of DCS, but for suspected cases, there is no definitive diagnostic test, and clinicians instead rely on observing symptoms and seeing whether patients respond to hyperbaric oxygen (HBO) therapy, which involves breathing oxygen at high pressures. While HBO resolves the symptoms in 80–90% of cases, the authors also noted that the effects may be long-lasting, and “ … victims may suffer from long-term sequelae.” DCS involving the spinal cord is particularly challenging to treat, they pointed out, and may result in permanent paraplegia or paraparesis, bladder dysfunction and incontinence, and sexual dysfunction. However, they continued, “The search for new treatments for DCS as adjuncts to HBO and fluid resuscitation has so far been largely unsuccessful.”
Studying the transcriptome of divers could feasibly provide new insights into gene expression changes and pathophysiologic pathways and mechanisms that drive DSC. “Potentially, this can serve as a stepping stone towards the identification of novel biomarkers or druggable targets,” the investigators suggested. Animal models have already demonstrated upregulation of proinflammatory signaling molecules in DCS. But, while uneventful diving and DCS can both trigger changes in the peripheral blood transcriptome, distinguishing physiological responses from pathological changes in humans remains “a major challenge.” And as the scientists continued, “To the best of our knowledge, no study has evaluated a DCS-induced transcriptomic signature in humans.”
To investigate transcriptomic changes associated with decompression sickness, the researchers took blood samples from seven divers who had been diagnosed with DCS after a deep dive, and from another six divers who had completed a dive without developing any signs of DCS. Blood samples were taken from each of the divers at two distinct times, first within 8 hours of their emerging from the water, and again 48 hours afterward, when the divers with decompression sickness had undergone hyperbaric oxygen treatment. The team performed RNA sequencing analysis to measure gene expression changes in white blood cells, and relate their functions to biological pathways. The results showed that in DCS cases there was an enrichment of transcripts involved in acute inflammation, activation of innate immunity and free radical scavenging pathways, “… with specific upregulation of transcripts related to neutrophil function and degranulation,” the team wrote. “We show that cutaneous DCS elicits the differential expression of several transcripts involved in leukocyte activity, inflammation, and cytokine production, with prominent perturbation of genes in the PI3K-AKT and TLR pathway. In fresh DCS cases within 8 hours of surfacing from diving, upregulated transcripts are characteristic of the leukocyte myeloid lineage—specifically granulocytes.”
Interestingly, the DCS-induced transcriptomic changes were reversed at the second time-point, after the individuals had received hyperbaric oxygen therapy. The team said the findings provide a first step towards potentially developing a diagnostic test for decompression sickness, and may also point to new treatment targets. “To the best of our knowledge, this is the first study that evaluates DCS-induced transcriptomic alterations in man,” they commented. “This study sheds light on the inflammatory pathophysiology of DCS and the associated immune response. Such data may potentially be valuable in the search for novel treatments targeting this disease.”
“We hope that our findings can aid the development of a blood-based biomarker test for human decompression sickness that can facilitate diagnosis or monitoring of treatment response,” said co-author Ingrid Eftedal, PhD, of the Norwegian University of Science and Technology. “This will require further evaluation and replication in larger groups of patients.”