Treatment of idiopathic pulmonary fibrosis with glycogen synthase kinase 3 form beta inhibitors
A pulmonary fibrosis, idiopathic technology, applied in the field of treating idiopathic pulmonary fibrosis
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Embodiment I
[0144] Materials and methods and two models of pulmonary fibrosis
[0145] All animal studies were approved by the Institutional Animal Care and Use Committee of the University of Texas Health Science Center at Tyler. C57BL / 6 mice (10 to 12 weeks old, approximately 20 g (from Jackson Laboratory, Bar Harbor ME)) were first anesthetized with xylazine / ketamine by intraperitoneal (IP) injection. Lung injury was then induced according to (Sisson TH et al., Am J Pathol 2015, 185:969-860) with some modifications. Bleomycin sulfate (Teva, 0.8 units / kg) was administered intratracheally via an endotracheal tube. Animals were monitored daily for signs of respiratory distress, significant weight loss, or moribund state. The control group received normal saline under the same conditions.
[0146] Treatment started 14 days after injury initiation. For GSK-3β inhibitor studies, 9-ING-41 (gifted by Actuate Therapeutics, Ft. Worth, TX) at 30 mg / kg (gifted by Actuate Therapeutics, Ft. Wor...
Embodiment II
[0151] 9-ING-41 ameliorates bleomycin-mediated reduction in lung function and volume
[0152] Such as Figures 1A to 1BGSK-3β inhibition with 9-ING-41 attenuated lung fibrosis as shown in . C57Bl / 6J mice were intratracheally administered bleomycin sulfate (0.8 U / kg) and 14 days later, treated with DMSO (vehicle) or the GSK-3β inhibitor 9-ING-41 (30 mg / kg) . Drugs were delivered by intraperitoneal (ip) injection in a volume of 40 μl for up to 14 days. At the completion of the 28-day course, lung compliance was determined using the Scireq flexivent. Lung representations were also collected by gated CT scans. These reproductions are then used to determine lung volumes. 9-ING-41 treatment significantly improved the decrease in lung compliance (p=0.04) and volume (p=0.026).
Embodiment III
[0154] 9-ING-41 Treatment Blocks Collagen Deposition in Bleomycin-Induced Lung Fibrosis: Trichrome
[0155] Lung tissue sections (5 μm) were prepared from vehicle- and 9-ING-41-treated. Sections were deparaffinized and trichrome stained to detect changes in lung architecture and collagen deposition (trichrome images not shown). Images were acquired at 2OX and represent 30 fields / slide / mouse, n=6 animals / treatment.
[0156] Foci of fibrosis consistent with bleomycin-induced pulmonary fibrosis were found throughout the injured lung. Areas of matrix deposition were readily and uniformly present throughout the lung. 9-ING-41-treated mice also showed areas of injury; however, these areas were fewer in number and smaller than those found in vehicle-treated animals. In addition, compared with the DMSO-treated control ( Figure 2B ) compared to ( Figure 2A ), collagen deposition in fibrotic lesions was generally reduced. see also Figures 5A to 5F .
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