Pilot study of the antifibrotic effects of the multikinase inhibitor pacritinib in a mouse model of liver fibrosis

Figures & data

Table 1 Treatment schedule for all groups during weeks 6–9

Test substance	Dose (mg/kg)	Volume (mg/kg)	Regimens	Death (week)
Vehicle	NA	10	Oral, twice daily, 6–9 weeks	9
Pacritinib	200	10	Oral, twice daily (day 0 to morning of day 10)	9
	150	10	Oral, twice daily (afternoon of day 10 to day 21)
Telmisartan	10	10	Oral, once daily, 6–9 weeks	9

Abbreviation: NA, not applicable.

Figure 1 Body-weight changes in all treatment groups (n=8 per group). *P<0.05, telmisartan vs vehicle.

Figure 2 (A) Body weight, (B) liver weight, and (C) liver:body weight ratio on day of death.

Abbreviation: NS, not significant.

Figure 3 Representative micrography of H&E-stained liver sections on day of death.

Abbreviation: H&E, hematoxylin and eosin.

Figure 4 NAFLD-activity scores for all groups on day of death.

Abbreviations: NAFLD, nonalcoholic fatty-liver disease; NS, not significant.

Figure 5 Representative photomicrographs of Sirius red-stained liver sections on day of death.

Table 2 Nonalcoholic fatty-liver disease-activity score³⁹

Group	n	Steatosis				Lobular inflammation				Hepatocyte ballooning
		0	1	2	3	0	1	2	3	0	1	2
Vehicle	8	–	6	2	–	–	1	6	1	–	1	7	5.1±0.6
Pacritinib	5	3	2	–	–	–	2	1	2	1	2	2	3.6±1.5
Telmisartan	7	3	4	–	–	1	5	1	–	2	1	4	2.9±1.6

Figure 6 Plasma levels of CK18 fragment M30 on day of death.

Figure 7 Inflammation pathways and potential pacritinib intervention points in fibrosis.

Notes: In peripheral blood monocytes, fibroblasts and endothelial cells, binding of IL1β induces IL6 secretion in a process involving IRAK1. Observed phenotypic reductions in IL6 levels induced by pacritinib may reflect IRAK1 inhibition, with downstream effects on inflammation, fibroblast activation, and fibrosis. Upper schema: in naïve T cells, binding of IL6 (together with TGFβ) ultimately induces differentiation into T_H17 cells. Both JAK2 and IRAK1 (both of which pacritinib inhibits) are necessary for STAT3 activation; activated STAT3 dimerizes and translocates to the nucleus, where it binds to DNA, leading to expression of the transcription factor RORγt, which is critical for T_H17-cell differentiation, and export of IL23R. In T_H17 cells, IL23 binds to the IL23R/IL12Rβ1 receptor to activate STAT3 in another JAK2-dependent process; binding of the STAT3 dimer promotes expression of IL17A, while binding of RORγt promotes the expression of IL17A and IL17F, both of which are secreted by T_H17 cells, leading to neutrophil recruitment and infiltration and downstream inflammation and fibrosis. Lower schema: IL6 acts as a switch to induce differentiation of monocytes to macrophages rather than dendritic cells; a second critical factor in monocyte differentiation is CSF1R, the kinase activity of which pacritinib also inhibits; macrophages secrete the proinflammatory cytokines TNFα, IL1β, and IL6, which are involved in fibroblast activation.
Abbreviations: Pac, pacritinib; PBMCs, peripheral blood mononuclear cells; ECs, endothelial cells.

KleinerDEBruntEMvan NattaMDesign and validation of a histological scoring system for nonalcoholic fatty liver diseaseHepatology20054161313132115915461

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