Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

Kim, Yu-Mee; Haghighat, Leila; Spiekerkoetter, Edda; Sawada, Hirofumi; Alvira, Cristina M.; Wang, Lingli; Acharya, Shinjita; Rodriguez-Colon, Gabriela; Orton, Andrew; Zhao, Mingming; Rabinovitch, Marlene

doi:10.1016/j.ajpath.2011.05.051

Cited by 77 publications

(68 citation statements)

References 65 publications

(85 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Elastase inhibition reverses muscularization of DPAs in the monocrotaline rat model (16) and attenuates neointima formation in S100A4 overexpressing mice infected with murine gamma herpes virus (22). We speculate that in the Su/Hx rat the initial PAEC injury triggers PASMC activation and subsequent release of elastase identified as neutrophil elastase (22). The early inflammatory component of the Su/Hx model (38) may be important in perpetuating activity of elastase and perhaps other proteases, notably proteinase-3, which is also inhibited by elafin (39).…”

Section: Discussionmentioning

confidence: 99%

“…Lung tissue was snap frozen in liquid N 2 and stored at 280 8 C for measurement of serine elastase activity by the DQ-elastin substrate assay (22).…”

Section: Elastase Assaymentioning

confidence: 99%

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Elafin Reverses Pulmonary Hypertension via Caveolin-1–Dependent Bone Morphogenetic Protein Signaling

Nickel

Spiekerkoetter²,

Gu³

et al. 2015

Am J Respir Crit Care Med

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129

135

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Rationale: Pulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown.Objectives: To assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism.Methods: Rats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/ hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling. Measurements and Main Results:In Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of endothelial surface caveolin-1.Conclusions: Elafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Elafin Reverses Pulmonary Hypertension via Caveolin-1–Dependent Bone Morphogenetic Protein Signaling

Nickel

Spiekerkoetter²,

Gu³

et al. 2015

Am J Respir Crit Care Med

Self Cite

129

135

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“…Similarly, transfection of a dominant-negative survivin construct (114) blocked a downstream effector of growth factor signaling and was also effective in reversing PAH through SMC apoptosis. Recently, we found that the relevant PA SMC elastase in PAH is neutrophil elastase (115). PA SMCs from mice that overexpress S100A4 have elevated levels of neutrophil elastase mRNA and protein, as do PA SMCs from patients with IPAH.…”

Section: Elastase Activitymentioning

confidence: 99%

Molecular pathogenesis of pulmonary arterial hypertension

Rabinovitch¹

2012

J. Clin. Invest.

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680

646

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Pathological features of PAHPulmonary arterial hypertension (PAH) is diagnosed by an elevation in mean pulmonary arterial (PA) pressure above 25 mmHg at rest or 30 mmHg with exercise. Patients usually present with much higher levels of PA pressure, but only vague and insidious symptoms of increasing fatigue and dyspnea; some patients are diagnosed only after syncopal episodes, which can reflect suprasystemic levels of PA pressure and low cardiac output. The causes of PAH were reclassified according to a consensus at the Fourth World While this review focuses on pulmonary hypertension category 1 (i.e., PAH), pathophysiologic insights can also be gained from understanding other causes of pulmonary hypertension. Hence, experimental studies in hypoxic animals are also discussed.In neonates and in infants, PAH likely results from failure of the neonatal pulmonary vasculature to dilate at birth, and pathological changes in the blood vessels are evident in the first few days of life. Most prominent is abnormal muscularization of distal PAs at the alveolar duct and wall levels and a striking reduction in their number. In older infants and adults, there is also progressive intimal hyperplasia leading to occlusive changes in the PAs and plexiform lesions (Figure 1 and see below).PA EC alterations in the clinical (2) and experimental (3) setting precede muscularization of distal PAs. In PA ECs from patients with idiopathic PAH (IPAH), an increase in Tie2 receptor expression in ECs releases serotonin, mediating SMC proliferation (4). Dysfunctional ECs can either release factors that stimulate SMC proliferation, such as FGF-2 (5), or fail to produce agents that normally suppress proliferation of SMCs in response to growth factors, such as apelin (encoded by Apln) (6).Muscularization of distal, normally nonmuscular, PAs at the alveolar duct and wall level is associated with differentiation of pericytes into SMCs that subsequently proliferate. The progressive thickening of the wall of more proximal intraacinar and preacinar muscular arteries and the obliteration associated with neointimal formation are attributed to increased proliferation and migration of cells considered to be SMCs because they are α-SMA positive (7). The origin of these cells is unclear, and the mechanism of their dysregulation is the subject of intense study. They may represent a specialized subpopulation of SMCs; they may originate as stem cells (8) or fibrocytes (9) or transform from ECs (10, 11). The loss of distal PAs could be caused by alterations in ECs and/or pericytes resulting in apoptosis (12).Later in disease, there is dysregulated EC proliferation, producing aberrant channels in the otherwise obliterated lumen of the vessel and in the adventitia (i.e., the plexiform lesion). These channels may reflect clonal expansion of apoptosis-resistant ECs (13), or they may be derived from circulating endothelial progenitor cells (EPCs) that accumulate at sites of endothelial denudation or injury and expand locally (14). PA ECs from patients with IPAH prod...

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“…Primary mouse PASMC (mPASMC) were isolated from control (Cre-ET-1 flox/flox ) and SM22␣-ET-1 Ϫ/Ϫ mice using a modified elastase/collagenase digestion protocol (18). PA tissue was digested in dispersion medium containing 40 mol/l CaCl2, 0.5 mg/ml elastase (Worthington Biochemical), 0.5 mg/ml collagenase (Worthington Biochemical), 0.2 mg/ml soybean trypsin inhibitor (Worthington Biochemical), and 2 mg/ml albumin (Sigma-Aldrich) for 20 min at 37°C.…”

Section: Generation Of Sm22␣-et-1mentioning

confidence: 99%

Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia

Kim

Barnes

Ying

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22␣-Cre mice with ET-1 flox/flox mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22␣ promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O 2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1 ϩ/ϩ and ET-1 Ϫ/Ϫ mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22␣-ET-1 Ϫ/Ϫ and SM22␣-ET-1 ϩ/ϩ (control) littermates. After exposure to hypoxia (10% O 2, 21-24 days), RVSP was and vascular remodeling were less in SM22␣-ET-1 Ϫ/Ϫ mice compared with control littermates (P Ͻ 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC. pulmonary hypertension; smooth muscle cells AT ALL POINTS IN ORGANISMAL DEVELOPMENT AND LIFE, control of pulmonary vascular tone is of critical importance. During fetal life, normal lung development requires closely circumscribed pulmonary flow, while pulmonary vascular resistance (PVR) exceeds systemic vascular resistance. With the onset of airbreathing life, PVR must decrease abruptly to accommodate the increase in pulmonary blood flow that enables gas exchange (3, 4). Early in postnatal life, PVR decreases still further to 20% of systemic vascular resistance, where, under normal conditions (6), it remains throughout the remainder of air-breathing life.However, in a number of pathological states, pulmonary arterial pressure is increased, leading to profoundly untoward consequences. For example, in the perinatal period, pulmonary vasodilation is biologically imperative. If PVR does not decrease with the onset of air-breathing life, persistent pulmonary hypertension of the newborn results in a substantial cause of neonatal morbidity and mortality (25). During air-breathing life, increases in pulmonary vascular tone possess even more profound untoward consequences.Pulmonary arterial hypertension (PAH) is a syndrome wherein...

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Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

Cited by 77 publications

References 65 publications

Elafin Reverses Pulmonary Hypertension via Caveolin-1–Dependent Bone Morphogenetic Protein Signaling

Elafin Reverses Pulmonary Hypertension via Caveolin-1–Dependent Bone Morphogenetic Protein Signaling

Molecular pathogenesis of pulmonary arterial hypertension

Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia

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