C1 Esterase Inhibitor Reduces Lower Extremity Ischemia/Reperfusion Injury and Associated Lung Damage

Duehrkop, Claudia; Banz, Yara; Spirig, Rolf; Miescher, Sylvia; Nolte, Marc W.; Spycher, M. A.; Smith, Richard A.; Sacks, Steven H.; Rieben, Robert

doi:10.1371/journal.pone.0072059

Cited by 30 publications

(27 citation statements)

References 59 publications

(61 reference statements)

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“…The complex signaling pathways and markedly unpredictable interpatient heterogeneity of IPF contribute to the disappointing outcomes of many clinical trials. Complement activation, a key component of the innate immune system, is triggered in response to multiple types of tissue injury (2)(3)(4)(5)(6)(7)(8)(9)(10). Previous studies have reported immune complexes in IPF that could activate complement (11), whereas more recent studies have reported the presence of complement activation products in patients with IPF and that the alternative pathway, fragment Ba, was clinically relevant as an indicator of disease severity (12).…”

mentioning

confidence: 99%

Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

Fisher

Mickler

et al. 2016

FASEB j.

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Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Whereas we have previously reported elevated anaphylatoxins—complement component 3a (C3a) and complement component 5a (C5a)—in IPF, which interact with TGF‐β and augment epithelial injury in vitro, their role in IPF pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors (C3aR and C5aR) in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of C3aR and C5aR in lung fibrosis by using bleomycin‐injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition (Masson's trichrome, hydroxyproline, collagen type I α 1 chain, and collagen type I α 2 chain). Pharmacologic or RNA interference‐specific interventions suppressed complement activation (C3a and C5a) and soluble terminal complement complex formation (C5b‐9) locally and active TGF‐β1 systemically. C3aR/C5aR antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn. Clinically, compared with pathologically normal human subjects, patients with IPF presented local induction of C5aR, local and systemic induction of soluble C5b‐9, and amplified expression of C3aR/C5aR in lesions. The blockade of C3aR and C5aR arrested the progression of fibrosis by attenuating local complement activation and TGF‐β/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.—Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters‐Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB J. 30, 2336–2350 (2016). http://www.fasebj.org

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confidence: 99%

Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

Fisher

Mickler

et al. 2016

FASEB j.

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“…DuehRkop et. al., [7] affirms that C1 INH may provide a promising therapy to reduce peripheral IRI as well distant lung injury in complicated and prolonged surgical interventions requiring tourniquet application.…”

Section: C1 Esterase Inhibitor (C1 Inh)mentioning

confidence: 69%

“…The etiology of Port-Revascularization Syndrome is not fully known, but it is accepted as a multifactorial chain with a time-dependent molecular and structural change of the affected tissues: inflammatory cascades are activated with excessive complement deposition on the vascular endothelium; endothelial cells and white blood cells are activated; great production of free radicals responsible for increasing capillary permeability, edema and cell aggregation; and release of vasoactive factor that causes further damage to local and remote tissues [3,7].…”

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confidence: 99%

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Treatment of Post-Revascularization Syndrome: brief communication

Freitas¹,

Martins²,

Lima³

et al. 2015

Int Arch Med

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Post-Revascularization Syndrome (PRS), also described as, Ischemic Reperfusion Injury (IRI), is the main cause of failure in the revascularization of limbs. The etiology of Port-Revascularization Syndrome is not fully known, but it is accepted as a multifactorial chain with a time-dependent molecular and structural change of the affected tissues. Current clinical treatments of PRS are supportive only notwithstanding numerous intervention strategies have been proposed aiming at reducing IRI. The present perspective aimed to explain all the available treatments in studies of IRI, and their potential effects in the future medicine. Since there are almost no articles covering this topic, we believe that this perspective will clarify the necessity of more researchers and studies on IRI. Our main findings leads to believe that there are many possible therapies for ischemic reperfusion injury, but most of them are still not used in practical scenarios because of it small samples studies, or in vitro techniques or the clinical trials are still not concluded. Although, significant work remains to be done. Contact information:Modesto Leite Rolim Neto. modestorolim@yahoo.com.br KeywordsPost-Revascularization Syndrome; Treatment; Review.Post-Revascularization Syndrome (PRS), also described as, Ischemic Reperfusion Injury (IRI), is the main cause of failure in the revascularization of limbs and the transfer of free flaps with 'non reflow' phenomenon [1]. It involves microcirculatory collapse during revascularization following an ischemic insult, that constitutes an acute inflammatory process by which cells are damaged first by temporary ischemia, hypoxia and accumulation of toxic metabolites and later by reperfusion [2,3]. It may result from thrombotic occlusion, embolism, trauma or surgical intervention through tourniquet application and subsequent restoration of blood flow.

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“…Most studies have attempted to show that one drug will make a difference, and regarding I/R lesion in vitro experiments and preclinical studies have shown good results. Nonetheless, the lesion is manifested systemically and affects several processes; therefore, the correct approach needs several drugs targeting the physiopathological process (Figure 3) [1–3, 55, 64, 65, 75, 92, 94, 95, 100, 104, 183–185]. …”

Section: Analysis Of the Pharmacological Approach In I/rmentioning

confidence: 99%

Alternative Interventions to Prevent Oxidative Damage following Ischemia/Reperfusion

Rodríguez-Lara

Cardona-Muñoz

Ramírez-Lizardo

et al. 2016

Oxidative Medicine and Cellular Longevity

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Ischemia/reperfusion (I/R) lesions are a phenomenon that occurs in multiple pathological states and results in a series of events that end in irreparable damage that severely affects the recovery and health of patients. The principal therapeutic approaches include preconditioning, postconditioning, and remote ischemic preconditioning, which when used separately do not have a great impact on patient mortality or prognosis. Oxidative stress is known to contribute to the damage caused by I/R; however, there are no pharmacological approaches to limit or prevent this. Here, we explain the relationship between I/R and the oxidative stress process and describe some pharmacological options that may target oxidative stress-states.

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C1 Esterase Inhibitor Reduces Lower Extremity Ischemia/Reperfusion Injury and Associated Lung Damage

Cited by 30 publications

References 59 publications

Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

Treatment of Post-Revascularization Syndrome: brief communication

Alternative Interventions to Prevent Oxidative Damage following Ischemia/Reperfusion

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