Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

Angelini, Daniel J.; Su, Qingning; Yamaji-Kegan, Kazuyo; Fan, Chunling; Teng, Xingwu; Hassoun, Paul M.; Yang, Stephen C.; Champion, Hunter C.; Tuder, Rubin M.; Johns, Roger A.

doi:10.1165/rcmb.2008-0271oc

Cited by 56 publications

(68 citation statements)

References 42 publications

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“…PT-specific changes revealed an upregulation of resistin-like gamma (retnlg in mice and RETNLB in humans), which codes for a secreted protein linked to scleroderma-associated pulmonary hypertension in humans (6). RETNLB induces the proliferation of primary human pulmonary smooth muscle and endothelial cells (6) and may contribute to airway remodeling in asthma (27). Pulmonary hypertension can also be associated with compromised connective tissue (32).…”

Section: Resultsmentioning

confidence: 99%

Pertussis Toxin Exacerbates and Prolongs Airway Inflammatory Responses during Bordetella pertussis Infection

2012

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Throughout infection, pathogenic bacteria induce dramatic changes in host transcriptional repertoires. An understanding of how bacterial factors influence host reprogramming will provide insight into disease pathogenesis. In the human respiratory pathogen Bordetella pertussis, the causative agent of whooping cough, pertussis toxin (PT) is a key virulence factor that promotes colonization, suppresses innate immune responses during early infection, and causes systemic disease symptoms. To determine the full extent of PT-associated gene regulation in the airways through the peak of infection, we measured global transcriptional profiles in the lungs of BALB/c mice infected with wild-type (WT) or PT-deficient (⌬PT) B. pertussis. ⌬PT bacteria were inoculated at a dose equivalent to the WT dose and at a high dose (⌬PT high ) to distinguish effects caused by higher bacterial loads achieved in WT infection from effects associated with PT. The results demonstrated that PT was associated with a significant upregulation of immune and inflammatory response genes as well as several other genes implicated in airway pathology. In contrast to the early, transient responses observed for ⌬PT high infection, WT infection induced a prolonged expression of inflammatory genes and increased the extent and duration of lung histopathology. In addition, the administration of purified PT to ⌬PT high -infected mice 1 day after bacterial inoculation exacerbated and prolonged inflammatory responses and airway pathology. These data indicate that PT not only is associated with exacerbated host airway responses during peak B. pertussis infection but also may inhibit host mechanisms of attenuating and resolving inflammation in the airways, suggesting possible links between PT and pertussis disease symptoms.

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Section: Resultsmentioning

confidence: 99%

Pertussis Toxin Exacerbates and Prolongs Airway Inflammatory Responses during Bordetella pertussis Infection

2012

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“…Allergic responses to ovalbumin or to Aspergillus species in mice can also cause extensive spotty pulmonary vascular remodeling, without pulmonary hypertension (88). In this model, an IL-13-mediated increase in α-resistin is associated with SMC proliferation, but the functional significance of this molecule in scleroderma and PAH (89) and in experimental schistosomiasis (87) is not known. In mice lacking prostaglandin synthase, induction of allergic inflammation with the house dust mite induces intense pulmonary vascular remodeling, changes that are reversed by administration of prostaglandin E 2 (90).…”

Section: Inflammation and Immune Mechanismsmentioning

confidence: 99%

Molecular pathogenesis of pulmonary arterial hypertension

Rabinovitch¹

2012

J. Clin. Invest.

680

649

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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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“…In comparison to historical data, those outcomes appeared to be better than expected. A number of studies in 2009 have characterized patients with CTD-PAH (16,17) as well as evaluating new candidate molecules for potential targeted therapy of this patient population (18). Condliffe and colleagues have now provided important new data from a reasonably sized patient group from the United Kingdom that might challenge the previous survival estimates (19).…”

Section: Update On Special Clinical Conditions Associated With Pulmonmentioning

confidence: 99%