title: Insulin-like growth factor-1 binding protein 3 (IGFBP-3) promotes recovery from trauma-induced expression of inflammatory and apoptotic factors in retina.
abstract: Ocular trauma affects 20% of Americans in their lifetime and can cause permanent visual system damage. We have used a mouse model of ocular trauma (exposure to an air blast from a paintball gun) to examine pathways that trigger the resulting retinal damage and to develop treatment strategies that might ameliorate the deleterious effects of trauma on retinal tissue. Our previous studies have shown that ocular blast causes an increase in protein levels of inflammatory mediators and apoptotic factors, including tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL-1β), as well as the apoptotic markers, Bax, cytochrome C, and cleaved caspase 3. Furthermore, topical treatment by eye drop application of a β-adrenergic receptor agonist, Compound 49b, was shown to decrease these inflammation/apoptosis markers and thus ameliorate the effects of blast trauma. We postulate that the protective effect of Compound 49b may be linked to its demonstrated ability to activate the β-adrenergic receptor and in turn trigger production of insulin-like growth factor binding protein 3 (IGFBP-3). In the current study, we tested this hypothesis using mice with minimal IGFBP-3 activity (IGFBP-3 knockdown mouse) vs. wildtype mice. We found that ocular blast alone did not affect IGFBP-3 levels in retinas of wild type or knockdown mice and surprisingly, the lower levels of IGFBP-3 in knockdown animals did not exacerbate the blast-induced increase in protein levels of inflammation/apoptosis markers. Nevertheless, the levels of IGFBP-3 were significantly increased in knockdown mouse retina by treatment with Compound 49b 24h post-trauma and as expected, the increase in IGFBP-3 was linked to a decrease in inflammation/apoptosis markers. We conclude that while lowered IGFBP-3 may not make the retina more vulnerable to blast injury, an increase in IGFBP-3 post-trauma may play an important role in limiting trauma-induced inflammatory and apoptotic pathways leading to retinal damage. Eye drop application of the β-adrenergic receptor agonist, Compound 49b, provides a promising treatment strategy for increasing IGFBP-3 levels to promote recovery from retinal inflammation and apoptosis after ocular blast.
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Youde
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Pagadala
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, United States; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, United States; Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, United States. Electronic address: jsteinl1@uthsc.edu.
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
mesh_terms: D000818:Animals; D017209:Apoptosis; D018836:Inflammation Mediators / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014947:Wounds and Injuries / Q000473:pathology*
chemical_list: D018836:Inflammation Mediators; D018972:Insulin-Like Growth Factor Binding Protein 3; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha
keywords: Apoptosis; IGFBP-3; IL-1B; Ocular blast; TNFa
references.citation: J Neuropathol Exp Neurol. 2011 May;70(5):399-416
references.pmid: 21487304
references.citation: Brain Res. 2005 Sep 28;1057(1-2):17-28
references.pmid: 16139821
references.citation: Endocrinology. 2007 Jan;148(1):354-62
references.pmid: 17008394
references.citation: Invest Ophthalmol Vis Sci. 2013 Aug 09;54(8):5376-84
references.pmid: 23868984
references.citation: Invest Ophthalmol Vis Sci. 2012 May 17;53(6):2913-20
references.pmid: 22603978
references.citation: Invest Ophthalmol Vis Sci. 2012 Oct 17;53(11):7220-6
references.pmid: 22977137
references.citation: Exp Eye Res. 2012 Jun;99:63-70
references.pmid: 22504073
references.citation: PLoS One. 2014 Apr 02;9(4):e93788
references.pmid: 24695399
references.citation: Invest Ophthalmol Vis Sci. 2012 May 17;53(6):3004-13
references.pmid: 22467575
references.citation: Apoptosis. 2013 Mar;18(3):361-8
references.pmid: 23291901
references.citation: N Engl J Med. 2011 Jun 2;364(22):2172-3
references.pmid: 21631351
references.citation: J Neuroinflammation. 2013 Jul 30;10:96
references.pmid: 23899290
references.citation: Invest Ophthalmol Vis Sci. 2013 Apr 30;54(4):3052-7
references.pmid: 23557743
references.citation: Front Neurol. 2010 Dec 10;1:151
references.pmid: 21206523