Can lipid 'SPMs' suppress inflammation?

From then on,Research on these stop signals, known academically as specialized pro-resolving mediators (SPMs), has exploded

A PubMed search for "lipoxin", the first identified SPMs, turned up more than 2,200 papers, and at least three biotech companies are planning clinical trials with synthetic molecules designed to restore or enhance the human body Natural anti-inflammatory powers that can wreak havoc if inflammation persists for too long

In a paper published last month in Frontiers in Pharmacology, an international group of 18 scientists, including experts in lipid analysis, argued that studies that identify these molecules in the human body often detect them at very high levels.

The paper's authors offer an even harsher criticism: The protocol developed by Serhan and his collaborators to detect SPMs in bodily fluid or tissue samples does not meet accepted standards, they say

Even some scientists who haven't joined the mainstream are struggling

Derek Gilroy, an immunology researcher at UCL, said he had worked with Selhan but was now moving his lab away from SPMs,He "has had a very negative experience dealing with these things, and seeing some of the data makes me wonder if these things are real

Neither university was willing to confirm the scientific explorations

"I'm confused," adds Mauro Perretti, an immunopharmacologist at QMUL who studies SPMs independently of Dalli but also collaborates with Serhan

"SPMs exist, they've been characterized in many ways, they've been synthesized, and they're active

In 1984, he discovered a new type of fatty acid produced by the human body

He visited Dalli's lab for advice, but said "they didn't teach me anything useful

In order for a sample to contain molecules such as lipids, scientists typically require a spike in the liquid chromatography-mass spectrometry data that is well above noise

Critics of the anti-inflammatory lipid study say several chromatograms in one paper did not show a clear peak

Valerie O'Donnell, a lipid biochemist at Cardiff University

About 3 years ago, while reviewing papers on SPMs, noticed some "strange" looking graphs showing the results of liquid chromatography-mass spectrometry (LCMS), which divides the molecular weight of a sample into ions with different molecular weights, producing A graph called a chromatogram

They found at least 70 papers from Serhan and Dalli's groups that contained what they considered suspicious chromatograms
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They made some criticism public last year
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in apreprintThe December 8, 2021 publication by the research team and other experts in lipid analysis highlights a 2020 paper by Dalli's group that identified a lipid in the serum of patients with early-stage rheumatoid arthritis toxin, a lipolysin and a marresol
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The article goes on to suggest that SPMs can serve as biomarkers for assessing patient response to drugs
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But critics say Dalli doesn't set a detection limit, which represents the lowest measurable concentration at which a molecule is present with high confidence
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Instead, they said, he used a method that did not meet accepted standards for biomolecular testing
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When O'Donnell and his colleagues applied the criteria described in the paper to inert methanol and buffers, they found that this indicated the presence of lipids where they were apparently absent
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O'Donnell and her colleagues concluded that Serhan and Dalli often quantify lipids by incorporating what critics consider "noise"

"We've never seen mass spectrometry quantification done this way before," Blair said
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Rebuttals posted this week on bioRxiv, Dalli, Serhan, and a colleague's preprint

Defend their approach by reanalyzing their LCMS dataUse the detection limits suggested in the preprint
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Dalli said the results confirmed his group's original results
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Dalli also noted that the analysis of blank samples on the lab's mass spectrometer yielded no false indications of SPMs
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no solution

But if they were right about the flaws in their analysis, how did the papers get through peer review and get published?

Fitzgerald says there are few experts in mass spectrometry of low-abundance lipids
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As a result, submissions on SPMs are often only addressed to experts in the specific disease being studied, who do not necessarily understand the complexities of mass spectrometry
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Critics also pointed out that journals prefer to publish positive results rather than negative test results
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Fitzgerald said nearly all of the positive results came from labs not associated with Selhan, and only a handful, including Selhan's, were responsible for analytical chemistry
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"We have an incentive to correct the literature," said Fitzgerald, whose own skepticism of SPMs dates back to 2015, whenHis team foundThe formation of SPMs in the urine or plasma of healthy volunteers was not associated with inflammation
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"I was happy that there wasn't any content at the time, so we stopped working on that," he said
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Fitzgerald and others

Not that lipoproteins, lysins, and other putative SPMs simply don't exist
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For example, some researchers have found them in people with COVID-19 or septic shock
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But they didn't find the signals in "the majority of biological samples," nor did they see convincing evidence that they worked to eliminate inflammation
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Selhan counters that just because other scientists have had trouble detecting biochemical components in human samples doesn't mean they don't matter
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"These modulators are made in the local environment, and when they're excreted in the blood or urine, they're out
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"There's no reason they'd be present at high levels in these samples, he said
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This is not just an academic debate
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Animal studies have shown that SPMs can quell inflammation, paving the way for clinical trials in humans
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A phase 1 trial of a lipoxin-based mouthwash published last year showed the drug was safe in patients with periodontal disease and showed some signs of efficacy
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Thetis Pharmaceuticals is planning trials of synthetic resolvins in patients with inflammatory bowel disease and cancer
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Two other biotech companies, OSE Therapeutics and ResoTher Pharma, are also developing drugs based on SPMs
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A single phase 1 trial designed to demonstrate safety does not demonstrate efficacy, Fitzgerald said
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But, he admits, "these high concentrations of chemicals have the potential to modulate the inflammatory response
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"Even if SPMs don't naturally address inflammation, it doesn't matter to drug developers whether synthetic drugs still address inflammation
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Selhan stands firm:

"I've independently confirmed all the research work
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People can buy synthetic SPMs from several companies and they can use them for detection or functional studies
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That's why there are thousands of publications
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If I try to fool people eyes, I don't think you'll see positive results from clinical trials
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"

Scientists from both camps are scheduled to speak at a symposium at the end of June
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But no one expects this bitter dispute to be resolved easily
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