AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis

Jennifer Cross, Grant R. Stenton, Curtis Harwig, Csaba Szabo, Tiziana Genovese, Rosanna Di Paola, Emanuale Esposito, Salvatore Cuzzocrea, Lloyd F. Mackenzie

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background and Purpose: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. Experimental Approach: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or dexamethasone (1 mg·kg−1·d−1, i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or pirfenidone (90 mg·kg−1·d−1, p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. Key Results: Given prophylactically, AQX-1125 (10 and 30 mg·kg−1) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-β immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg−1) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg−1, the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg−1) with corresponding improvements in disease severity. Conclusions and Implications: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.

Original languageEnglish (US)
Pages (from-to)3045-3057
Number of pages13
JournalBritish Journal of Pharmacology
Volume174
Issue number18
DOIs
StatePublished - 2017
Externally publishedYes

Fingerprint

Pulmonary Fibrosis
Bleomycin
Lung
Phosphatidylinositol 3-Kinases
Collagen
4-(4-(aminomethyl)-7a-methyl-1-methylideneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol
Lung Injury
Therapeutic Uses
Leukocyte Count
Phosphoric Monoester Hydrolases
Dexamethasone
Disease Progression
Neutrophils
Fibrosis

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cross, J., Stenton, G. R., Harwig, C., Szabo, C., Genovese, T., Di Paola, R., ... Mackenzie, L. F. (2017). AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis. British Journal of Pharmacology, 174(18), 3045-3057. https://doi.org/10.1111/bph.13934

AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis. / Cross, Jennifer; Stenton, Grant R.; Harwig, Curtis; Szabo, Csaba; Genovese, Tiziana; Di Paola, Rosanna; Esposito, Emanuale; Cuzzocrea, Salvatore; Mackenzie, Lloyd F.

In: British Journal of Pharmacology, Vol. 174, No. 18, 2017, p. 3045-3057.

Research output: Contribution to journalArticle

Cross, J, Stenton, GR, Harwig, C, Szabo, C, Genovese, T, Di Paola, R, Esposito, E, Cuzzocrea, S & Mackenzie, LF 2017, 'AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis', British Journal of Pharmacology, vol. 174, no. 18, pp. 3045-3057. https://doi.org/10.1111/bph.13934
Cross, Jennifer ; Stenton, Grant R. ; Harwig, Curtis ; Szabo, Csaba ; Genovese, Tiziana ; Di Paola, Rosanna ; Esposito, Emanuale ; Cuzzocrea, Salvatore ; Mackenzie, Lloyd F. / AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis. In: British Journal of Pharmacology. 2017 ; Vol. 174, No. 18. pp. 3045-3057.
@article{b1c2918304b9489fa0508745e9937194,
title = "AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis",
abstract = "Background and Purpose: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. Experimental Approach: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or dexamethasone (1 mg·kg−1·d−1, i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or pirfenidone (90 mg·kg−1·d−1, p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. Key Results: Given prophylactically, AQX-1125 (10 and 30 mg·kg−1) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-β immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg−1) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg−1, the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg−1) with corresponding improvements in disease severity. Conclusions and Implications: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.",
author = "Jennifer Cross and Stenton, {Grant R.} and Curtis Harwig and Csaba Szabo and Tiziana Genovese and {Di Paola}, Rosanna and Emanuale Esposito and Salvatore Cuzzocrea and Mackenzie, {Lloyd F.}",
year = "2017",
doi = "10.1111/bph.13934",
language = "English (US)",
volume = "174",
pages = "3045--3057",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "18",

}

TY - JOUR

T1 - AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis

AU - Cross, Jennifer

AU - Stenton, Grant R.

AU - Harwig, Curtis

AU - Szabo, Csaba

AU - Genovese, Tiziana

AU - Di Paola, Rosanna

AU - Esposito, Emanuale

AU - Cuzzocrea, Salvatore

AU - Mackenzie, Lloyd F.

PY - 2017

Y1 - 2017

N2 - Background and Purpose: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. Experimental Approach: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or dexamethasone (1 mg·kg−1·d−1, i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or pirfenidone (90 mg·kg−1·d−1, p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. Key Results: Given prophylactically, AQX-1125 (10 and 30 mg·kg−1) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-β immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg−1) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg−1, the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg−1) with corresponding improvements in disease severity. Conclusions and Implications: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.

AB - Background and Purpose: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. Experimental Approach: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or dexamethasone (1 mg·kg−1·d−1, i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg−1·d−1, p.o.) or pirfenidone (90 mg·kg−1·d−1, p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. Key Results: Given prophylactically, AQX-1125 (10 and 30 mg·kg−1) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-β immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg−1) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg−1, the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg−1) with corresponding improvements in disease severity. Conclusions and Implications: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.

UR - http://www.scopus.com/inward/record.url?scp=85028342308&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028342308&partnerID=8YFLogxK

U2 - 10.1111/bph.13934

DO - 10.1111/bph.13934

M3 - Article

VL - 174

SP - 3045

EP - 3057

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 18

ER -