Unopposed Cathepsin G, Neutrophil Elastase, and Proteinase 3 Cause Severe Lung Damage and Emphysema

Guyot, Nicolas; Wartelle, Julien; Malleret, Laurette; Todorov, Alexandre A.; Devouassoux, Gilles; Pachéco, Yves; Jenne, Dieter E.; Belaaouaj, Abderrazzaq

doi:10.1016/j.ajpath.2014.04.015

Cited by 97 publications

(116 citation statements)

References 53 publications

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“…The complications arise together with micro-embolisms, pulmonary artery hypertension and the alteration of the respiratory functions [41][42][43][44][45][46][47][48]. Neutrophils stimulation through different biochemical mechanisms produces high quantities of hydrogen peroxide [49][50][51]. The biosynthesised oxidants have a role in destroying bacteria, but the adverse effects produce a series of tissue inflammations.…”

Section: Biochemical Aspects Of Free Radicals and The Actions Of Oxidmentioning

confidence: 99%

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma — a review

Bedreag¹,

Rogobete

Sărăndan³

et al. 2015

Anaesthesiol Intensive Ther

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Multiple trauma patients require extremely good management and thus, the trauma team needs to be prepared and to be up to date with the new standards of intensive therapy. Oxidative stress and free radicals represent an extremely aggressive factor to cells, having a direct consequence upon the severity of lung inflammation. Pulmonary tissue is damaged by oxidative stress, leading to biosynthesis of mediators that exacerbate inflammation modulators. The subsequent inflammation spreads throughout the body, leading most of the time to multiple organ dysfunction and death. In this paper, we briefly present an update of biochemical effects of oxidative stress and free radical damage to the pulmonary tissue in patients in critical condition in the intensive care unit. Also, we would like to present a series of active substances that substantially reduce the aggressiveness of free radicals, increasing the chances of survival.

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Section: Biochemical Aspects Of Free Radicals and The Actions Of Oxidmentioning

confidence: 99%

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma — a review

Bedreag¹,

Rogobete

Sărăndan³

et al. 2015

Anaesthesiol Intensive Ther

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“…The level of cigarette smoke exposure in this rabbit model of emphysema is in line with the exposures seen in human disease; serum cotinine levels from smoke-exposed rabbits fall within the lower end of the serum cotinine range documented in the selfidentifying smokers in the National Health and Nutrition Examination Survey population (30). The proteolytic changes secondary to cigarette smoke seen in the rabbit model are documented to occur in the human disease (27,31,32) and in the mouse models (33)(34)(35). Cathepsin D is elevated in smoke exposure in both humans (36) and animal models (33), and we document in these studies the elevation of this protease in the rabbit smoke exposure model at an early time point.…”

Section: Discussionmentioning

confidence: 54%

Single-Photon Emission Computed Tomography/Computed Tomography Imaging in a Rabbit Model of Emphysema Reveals Ongoing Apoptosis In Vivo

Goldklang¹,

Tekabe²,

Zelonina³

et al. 2016

Am J Respir Cell Mol Biol

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Evaluation of lung disease is limited by the inability to visualize ongoing pathological processes. Molecular imaging that targets cellular processes related to disease pathogenesis has the potential to assess disease activity over time to allow intervention before lung destruction. Because apoptosis is a critical component of lung damage in emphysema, a functional imaging approach was taken to determine if targeting apoptosis in a smoke exposure model would allow the quantification of early lung damage in vivo. Rabbits were exposed to cigarette smoke for 4 or 16 weeks and underwent single-photon emission computed tomography/computed tomography scanning using technetium99m-rhAnnexin V-128. Imaging results were correlated with ex vivo tissue analysis to validate the presence of lung destruction and apoptosis. Lung computed tomography scans of long-term smoke-exposed rabbits exhibit anatomical similarities to human emphysema, with increased lung volumes compared with controls. Morphometry on lung tissue confirmed increased mean linear intercept and destructive index at 16 weeks of smoke exposure and compliance measurements documented physiological changes of emphysema. Tissue and lavage analysis displayed the hallmarks of smoke exposure, including increased tissue cellularity and protease activity. Technetium99m-rhAnnexin V-128 single-photon emission computed tomography signal was increased after smoke exposure at 4 and 16 weeks, with confirmation of increased apoptosis through terminal deoxynucleotidyl transferase dUTP nick end labeling staining and increased tissue neutral sphingomyelinase activity in the tissue. These studies not only describe a novel emphysema model for use with future therapeutic applications, but, most importantly, also characterize a promising imaging modality that identifies ongoing destructive cellular processes within the lung.

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“…17,20 A recent study indicated that active NsPs collectively caused more severe lung damage and enhanced the activity of tissue destructive proteases than HNE alone. 21 Although HNE is a traditional therapeutic target in neutrophilic inflammation, these findings indicate that this doctrine may no longer be valid; CatG and Pr3 are pathogenic proteases that are associated with the initiation and/or chronicity of lung inflammation and tissue injury.…”

Section: Effects Of Synthetics On Omentioning

confidence: 97%

Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3

Hwang¹,

Wang²,

Wang³

et al. 2015

Bioorganic & Medicinal Chemistry

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Unopposed Cathepsin G, Neutrophil Elastase, and Proteinase 3 Cause Severe Lung Damage and Emphysema

Cited by 97 publications

References 53 publications

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma — a review

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma — a review

Single-Photon Emission Computed Tomography/Computed Tomography Imaging in a Rabbit Model of Emphysema Reveals Ongoing Apoptosis In Vivo

Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3

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