A wide variety of human diseases — obesity, asthma, atherosclerosis, cancer, Alzheimer’s disease, and severe COVID-19 — have been linked to excessive inflammation. For four decades, Charles Serhan, D.Sc., Ph.D., has meticulously uncovered a new class of molecules — including some derived from the omega-3 fatty acids EPA and DHA — that play critical roles in the resolution of inflammation.

Serhan is the Simon Gelman Professor of Anesthesia at Harvard Medical School and Director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women’s Hospital. (Photo courtesy of Charles Serhan)

Serhan, a professor at Harvard Medical School and Brigham and Women’s Hospital, shared his insights into how inflammation ends during the 2022 Hans L. Falk Memorial Lecture on March 8.

“It is a real honor to present on behalf of Dr. Falk,” said Serhan. “As scientists, we all strive to have our contributions stand the test of time, and that’s clearly what has happened with Dr. Falk’s contributions.”

Falk was one of the founding scientific members of NIEHS and an internationally known cancer researcher and environmental health sciences leader. He joined NIEHS as associate director for laboratory research and later became associate director for health hazard assessment. NIEHS launched the Hans L. Falk Memorial Lecture Series in 1986, two years after Falk’s retirement and one year after his death.

A paradigm-changing discovery

Inflammation is the body’s process of protecting against injury or invading organisms. This process involves a flood of pro-inflammatory chemicals that evoke the cardinal signs of inflammation, which are heat, redness, swelling, and pain. The ideal outcome of all this activity, Serhan said, is the resolution of inflammation and a return to homeostasis. When that does not happen, inflammation becomes chronic and damages cells, tissues, and organs.

The resolution of inflammation was once believed to be a passive rather than an active process. Pro-inflammatory chemicals would, with time, become diluted in the bloodstream and simply disappear. But, as Serhan explained, that thinking changed when his laboratory uncovered a super-family of molecules — known as specialized pro-resolving mediators (SPMs) — whose main purpose is to actively stop inflammation. The discovery was a complete paradigm shift for the field, said NIEHS Staff Scientist Matthew Edin, Ph.D., who co-hosted the lecture alongside NIEHS Scientific Director Darryl Zeldin, M.D.

Recognizing Serhan’s work, Edin, left, said, “Rather than blocking inflammation with broad inhibitors like corticosteroids or trying to suppress components of the now famous cytokine storm, we have additional options for treating inflammation by activating resolution pathways.” (Photo courtesy of Steve McCaw / NIEHS)“There's a long list of Falk lecturers over the years, including Nobel laureates and other famous scientists,” Zeldin, right, told Serhan. “Maybe at some point, you'll be a Nobel laureate.” (Photo courtesy of Steve McCaw / NIEHS)

COVID-19 implications

According to Serhan’s research, SPMs work by limiting the magnitude and duration of the acute inflammatory response. One way they do that is by stopping the immune system from producing too many pro-inflammatory cytokines, lessening the so-called “cytokine storm” that can make diseases such as COVID-19 life-threatening.

Several studies have examined the role of SPMs in COVID-19 infections. Serhan said the consensus from this research is that low levels of SPMs are associated with poor outcomes.

Resolution pharmacology

Serhan’s studies have led to a new field called resolution pharmacology, which is focused on managing chronic inflammatory diseases. He explained that recent research has investigated whether supplements can increase SPMs and decrease inflammation, and thus far the results look promising.

“But you must be aware that over-the-counter fish oils are not the same as pure omega-3s,” he said, noting that fish oils also contain other substances such as fish steroids. “So, if you are thinking about supplementing, first eat some fish.”

Citations:
Serhan CN. 2014. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510(7503):92–101.

Serhan CN, Libreros S, Nshimiyimana R. 2022. E-series resolvin metabolome, biosynthesis and critical role of stereochemistry of specialized pro-resolving mediators (SPMs) in inflammation-resolution: Preparing SPMs for long COVID-19, human clinical trials, and targeted precision nutrition. Semin Immunol; doi:10.1016/j.smim.2022.101597 [Online 16 February 2022].

Hartling I, Cremonesi A, Osuna E, Lou PH, Lucchinetti E, Zaugg M, Hersberger M. 2021. Quantitative profiling of inflammatory and pro-resolving lipid mediators in human adolescents and mouse plasma using UHPLC-MS/MS. Clin Chem Lab Med 59(11):1811–1823.

Aoki S, Deyama S, Sugie R, Ishimura K, Fukuda H, Shuto S, Minami M, Kaneda K. 2022. The antidepressant-like effect of resolvin E1 in repeated prednisolone-induced depression model mice. Behav Brain Res 418:113676.

(Marla Broadfoot, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)