From the AGA Journals

Nerve growth factor therapy speeds gastric ulcer healing


Key clinical point: Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer (GU) healing, suggesting possible applications in human medicine.

Major finding: Compared with young individuals, elderly people have 5.5-fold lower NGF expression in their gastric mucosa.

Study details: A prospective study involving rats and humans, with NGF therapy performed in rats.

Disclosures: The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.

Source: Ahluwalia et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

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Ulcers on NSAIDs

Although the incidence of gastric ulcers has been declining in the general population, hospitalization and mortality linked to gastric ulcers remains high in the elderly population. One of the major risk factors for gastric ulceration is the use of NSAIDs. It is estimated that 40% of individuals aged 65 years and older fill at least one prescription for an NSAID each year. Given that the elderly population (those aged 65 years and older) is anticipated to more than double by the year 2050, reaching 84 million, understanding the pathogenesis of gastric ulceration is increasingly relevant.

Dr. Amy Christine Engevik

This study described a new role for nerve growth factor (NGF) in promoting angiogenesis during gastric ulcer repair. The authors observed that aged rats exhibited low NGF levels in gastric endothelial cells that corresponded with impaired ulcer healing of the gastric mucosa following injury. Local NGF treatment to aged rats significantly increased angiogenesis and gastric regeneration. Consistent with their in vivo rat model, analysis of human gastric biopsy specimens showed that individuals more than 70 years of age had decreased expression of NGF in gastric endothelial cells, compared with individuals younger than 40 years.

Ahluwalia and colleagues are the first to demonstrate the role of NGF in aging gastropathy, and their work highlights a key mechanism of angiogenesis during gastric repair that may inform future therapeutic strategies.

Amy Christine Engevik, PhD, is a postdoctoral fellow in the division of surgical sciences at Vanderbilt University Medical Center, Nashville, Tenn. She has no conflicts of interest.



Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

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