科羅拉多州奧羅拉健康科學中心以及科羅拉多州立大學兒童醫院的Ann C. Halbower醫師致電給Medscape胸腔醫學時評論，無疑的，我們看到經常過敏或是感染的兒童們並不會罹患長期扁桃體腺樣體組織過度增生。相反的反而是更常見的，那些經常有呼吸相關問題的兒童，扁桃腺與腺體較大，很顯然地，過敏與對扁桃腺體的效應是有基因傾向的。
麻州波士頓哈佛醫學院神經科副教授、兒童醫院兒童睡眠異常中心副主任Sanjeev V. Kothare醫師透過電子郵件向Medscape胸腔醫學評論，現在需要臨床研究來看標的治療對於PSPH的作用，看是否僅抑制扁桃體腺樣體異常增生，還是也會造成正常幹細胞複製的傷害。Kothare醫師表示，另一個問題是，使用這些針對PSPH藥物的最佳年齡。
Gene Upregulated in Pediatric Obstructive Sleep Apnea
By Robert Lowes
Medscape Medical News
February 10, 2010 — A new study has found that a gene coding for phosphoserine phosphatase, PSPH, is upregulated in the tonsils of children with obstructive sleep apnea (OSA). Inhibition of PSPH reduces lymphocyte proliferation and increases cell death, suggesting strategies for nonsurgical therapy in children with OSA.
The University of Chicago study, carried out in collaboration with the University of Louisville Pediatric Sleep Research Center, was published online January 21 in the American Journal of Respiratory and Critical Care Medicine.
OSA affects up to 3% of the pediatric population and is associated with metabolic, cardiovascular, and neurocognitive illnesses. Although studies have shown that exposure to smoking, allergies, and respiratory infections (RIs) may contribute to adenotonsillar hypertrophy, the mechanisms are not well understood. The usual treatment for children with OSA is surgical removal of tonsils and adenoids, with the attendant risk, pain, and expense.
"We are remarkably ignorant to this day as to why and how adenotonsillar tissues grow both physiologically and pathologically," senior author David Gozal, MD, from the Department of Pediatrics at the University of Chicago, Illinois, writes in an email to Medscape Pulmonary Medicine. "It is definitely possible that intrinsic immunologic and airway structural determinants may promote the growth of adenotonsillar tissues in the absence of all other factors." He pointed out that, interestingly, a sizable population of children experience recurring tonsillar infections without developing OSA.
"Certainly we've seen children who have frequent allergies or frequent infections that don't get long-term adenotonsillar hypertrophy," commented Ann C. Halbower, MD, from the Department of Pediatrics and the Children's Hospital Sleep Center, The Children's Hospital and University of Colorado, Denver, Health Sciences Center, Aurora, Colorado, by telephone to Medscape Pulmonary Medicine. "However the opposite is probably seen more often — those who have frequent respiratory issues do have large tonsils and adenoids...it seems quite apparent that there may be a genetic predisposition for both allergies and an effect on the tonsils," she noted.
The initial test population in this study consisted of children 6 to 11 years old, identified and recruited before surgery, undergoing tonsillectomies at Kosair Children's Hospital. The 18 OSA patients were consecutive, nonobese patients diagnosed at the Louisville center by polysomnographic testing and invited to participate. A comparison group matched by age, sex, and ethnicity consisted of 18 children with frequent RIs (at least 5 tonsillar infections in 6 months requiring antibiotics) but no sleep disorders.
Microarray RNA analysis of tonsillar tissue from all 36 children was followed by gene set enrichment analysis to identify gene sets enriched in OSA tissue. Of 1800 pathways investigated, 22 gene sets were enriched in OSA tissue, but none in RI tissue. Enriched gene sets fell into several functional categories, with genes involved in proliferation being the most numerous (564 genes).
Complex analyses of connectivity and differential expression narrowed the field to 69 genes, including some involved in regulation, inflammation signaling, or tissue growth. Investigators followed up on 2 of the "statistically significant network genes," DUSP1 and PSPH, both coding for protein phosphatases. Immunohistochemistry of tonsillar tissue cultures showed that PSPH protein expression localized in germinal centers and was more abundant in OSA than RI cultures.
Treating the cultures with increasing concentrations of protein phosphatase inhibitors okadaic acid or calyculin A produced concentration-dependent decreases in cell proliferation in cultures (n = 6) from OSA patients compared with control patients (for all 3 concentrations of okadaic acid, P < .05; for all 3 concentrations of calyculin A, P < .01). Effects of these inhibitors on cultures (n = 6) from patients with RIs were nonsignificant.
Thinking ahead to nonsurgical therapies for pediatric OSA, the authors cite studies showing that knockdown of PSPH expression in mice inhibited proliferation of neural stem cells. A single case of PSPH deficiency reported in a child involved growth and psychomotor retardation and facial abnormalities, as well as decreased PSPH activity in lymphoblasts and fibroblasts. Thus, systemic inhibition of PSPH would obviously be inappropriate.
"The idea for PSPH inhibition or knockdown would be to devise selective targeted delivery systems such as a liposome construct spray or other types of drug delivery vehicles that could be delivered locally to the affected tissues without going the systemic route," said Dr. Gozal. "It is possible that other strategies could be developed to selectively limit the drug/siRNA/other knockdown method to specific cells within the tonsils and adenoids," he added.
Sanjeev V. Kothare, MD, associate director, Center for Pediatric Sleep Disorders, Children's Hospital, and associate professor, Department of Neurology, Harvard Medical School, Boston, Massachusetts, commented by email to Medscape Pulmonary Medicine that clinical studies will be needed to see the effect of targeted therapy on PSPH, whether it not only inhibits adenotonsillar hypertrophy but causes other damage to normal stem cell proliferation. "Another issue is at what age to use these agents to target PSPH," noted Dr. Kothare.
"This initial work is really a demonstration of proof of concept," Dr. Gozal concluded. "Much work needs to be done to identify which gene or genes should be targeted, maybe in combination, to achieve the desired results."
Dr Gozal, Dr. Kothare, and Dr. Halbower have disclosed no relevant financial relationships.
Am J Respir Crit Care Med. Published online January 21, 2010.
