A Lymphocyte-Dependent Mode of Action for Imatinib Mesylate in Experimental Pulmonary Hypertension

Ormiston, Mark L.; Deng, Yupu; Rundle, Natalie T.; Bendjelloul, Farid; Tsoporis, James N.; Parker, Thomas G.; Stewart, Duncan J.; Courtman, David W.

doi:10.1016/j.ajpath.2013.01.031

Cited by 9 publications

(6 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When taken together, our findings support an emerging recognition of the capacity of NK cells to regulate the structure and integrity of vascular beds outside the uterus (23, 49) and provide some of the most compelling evidence to date of a role for NK cell impairment in the pathogenesis of PAH. These studies also build on previous work identifying a phenotypic and functional impairment of circulating NK cells in patients with PAH (31) and a potential role for these cells in the pathogenesis and treatment of PAH in rodent models of disease (32, 33). Ongoing and future studies will aim to clarify the precise molecular mechanisms underlying vascular dysfunction in these models of NK cell impairment.…”

Section: Discussionmentioning

confidence: 76%

See 1 more Smart Citation

Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency

Rätsep

Moore

Jafri

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3−/− mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.

show abstract

Section: Discussionmentioning

confidence: 76%

“…Although previous studies have demonstrated a role for NK cell stimulation in the mode of action of experimental pharmacological and cell-based PAH therapies (32, 33), it has not yet been determined if NK cell impairment is a driving factor in the initiation and progression of PAH or simply a consequence of established disease.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency

Rätsep

Moore

Jafri

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

show abstract

“…As reported, activation of JNK is involved in brain damage induced by hypertension and cerebral I/R (Sugino et al, 2000;Li et al, 2009;Hu et al, 2012;Ormiston et al, 2013). Activation of JNK enhances phosphorylation of c-Fos and c-Jun and facilitates AP-1 formation, which further triggers caspase-3-dependent or -independent signals, implicated in neuron death and memory loss (Tang et al, 2002;Guan et al, 2006).…”

Section: Discussionmentioning

confidence: 82%

Hypertension-mediated enhancement of JNK activation in association with endoplasmic reticulum stress in rat model hippocampus with cerebral ischemia-reperfusion

Yn¹,

Li²,

Chen³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. Acute brain ischemia can induce the activation of c-Jun N-terminal kinases (JNKs). Hypertension is a critical etiology for brain ischemia. We identified the effects of hypertension on the activation of JNK as well as its impact on SP600125, a JNK inhibitor, during endoplasmic reticulum stress (ERS) in the hippocampus using a rat model. Transient whole-brain ischemia was induced by 4-vessel occlusion (bilateral vertebral and bilateral common carotid arteries) in normal and spontaneous hypertensive rats. SP600125 (0.05 mg/kg, iv) was administered 30 min before ischemia. Morphological changes in hippocampal nerve cells were observed by cresyl violet staining. Phosphorylation of JNK, and expression levels of CHOP and GPR78, markers for ERS, were detected by western blot at 1, 6, 24, and 48 h, and 10981 JNK activation in cerebral ischemia-reperfusion ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (3): 10980-10990 (2015) neurological outcomes were measured using an eight-arm radial maze 48 h after ischemia. Hypertension apparently aggravated impairment of memory function, decreased the density of surviving neurons, increased phosphorylation of JNK, and enhanced CHOP expression, but reduced GPR78 levels in hippocampal tissues following brain ischemia. SP600125 alleviated neurological dysfunction, improved neuron survival, decreased phosphorylation of JNK and levels of CHOP, but increased expression of GPR78 in rats with hypertension during cerebral ischemia by inhibition of ERS.

show abstract

“…Additionally, the fact that cytokines/chemokines associated with lymphocytes were significantly downregulated supports previous reports that showed that lymphocyte accumulation, such as T cells and NK cells, is attenuated in the lungs of MCT-induced PAH rats. 55,56) Collectively, these results suggest that the therapeutic effect of pitavastatin-NP was mediated by inhibiting monocytemediated inflammation by blocking the MCP-1/CCR2 pathway in the lung. Some subtypes of PAH, such as systemic sclerosis-associated PAH, are known to be strongly associated with monocyte-mediated inflammation.…”

Section: Discussionmentioning

confidence: 86%

Nanoparticle-Mediated Targeting of Pitavastatin to Small Pulmonary Arteries and Leukocytes by Intravenous Administration Attenuates the Progression of Monocrotaline-Induced Established Pulmonary Arterial Hypertension in Rats

et al. 2018

View full text Add to dashboard Cite

Statins are known to improve pulmonary arterial hypertension (PAH) by their anti-inflammatory and antiproliferative effects in animal models. However, recent clinical studies have reported that clinically approved statin doses failed to improve clinical outcomes in patients with PAH. We therefore hypothesized that nanoparticle (NP)-mediated targeting of pitavastatin could attenuate the progression of established PAH. We induced PAH by subcutaneously injecting monocrotaline (MCT) in Sprague-Dawley rats. On day 14 after the MCT injection, animals that displayed established PAH on echocardiography were included. On day 17, they were randomly assigned to the following 5 groups: daily intravenous administration of (1) vehicle, (2) fluorescein-isothiocyanate-NP, (3) pitavastatin, (4) pitavastatin-NP, or (5) oral sildenafil. Intravenous NP was selectively delivered to small pulmonary arteries and circulating CD11b-positive leukocytes. On day 21, pitavastatin-NP attenuated the progression of PAH at lower doses than pitavastatin alone. This was associated with the inhibition of monocyte-mediated inflammation, proliferation, and remodeling of the pulmonary arteries. Interestingly, sildenafil attenuated the development of PAH, but had no effects on inflammation or remodeling of the pulmonary arteries. In separate experiments, only treatment with pitavastatin-NP reduced the mortality rate at day 35. NP-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes attenuated the progression of established MCT-induced PAH and improved survival. Therapeutically, pitavastatin-NP was associated with anti-inflammatory and anti-proliferative effects on small pulmonary arteries, which was completely distinct from the vasodilatory effect of sildenafil. Pitavastatin-NP can be a novel therapeutic modality for PAH.

show abstract

A Lymphocyte-Dependent Mode of Action for Imatinib Mesylate in Experimental Pulmonary Hypertension

Cited by 9 publications

References 47 publications

Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency

Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency

Hypertension-mediated enhancement of JNK activation in association with endoplasmic reticulum stress in rat model hippocampus with cerebral ischemia-reperfusion

Nanoparticle-Mediated Targeting of Pitavastatin to Small Pulmonary Arteries and Leukocytes by Intravenous Administration Attenuates the Progression of Monocrotaline-Induced Established Pulmonary Arterial Hypertension in Rats

Contact Info

Product

Resources

About