Tumstatin fragment selectively inhibits neutrophil infiltration in experimental asthma exacerbation

Nissen, Gyde; Hollaender, Henrike; Tang, Francesca; Wegmann, Michael; Lunding, Lars; Vock, Christina; Bachmann, Anna; Lemmel, Solveig; Bartels, Rainer; Oliver, Brian G.; Burgess, Janette K.; Becker, Tim; Kopp, Matthias; Weckmann, Markus

doi:10.1111/cea.13236

Cited by 18 publications

(19 citation statements)

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“…These functions favor the movement of neutrophils into the airways, congruent with airway neutrophilic inflammation that is characteristic of pasture-associated severe equine asthma. Increased neutrophil migration,65 chemotaxis,66,67 cell spreading,68 and infiltration60,69 have similarly been reported in human asthma. Our findings are also consistent with increased neutrophil migration70 and chemotaxis71,72 reported in barn-associated equine asthma.…”

Section: Discussionmentioning

confidence: 61%

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

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Dittmar

Nanduri

et al. 2019

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Background: Pasture-associated severe equine asthma is a warm season, environmentally-induced respiratory disease characterized by reversible airway obstruction, persistent and non-specific airway hyper-responsiveness, and chronic neutrophilic airway inflammation. During seasonal exacerbation, signs vary from mild to life-threatening episodes of wheezing, coughing, and chronic debilitating labored breathing. Purpose: In human asthma, neutrophilic airway inflammation is associated with more severe and steroid-refractory asthma phenotypes, highlighting a need to decipher the mechanistic basis of this disease characteristic. We hypothesize that the collective biological activities of proteins in bronchoalveolar lavage fluid (BALF) of horses with pasture-associated severe asthma predict changes in neutrophil functions that contribute to airway neutrophilic inflammation. Methods: Using shotgun proteomics, we identified 1,003 unique proteins in cell-free BALF from six horses experiencing asthma exacerbation and six control herdmates. Contributions of each protein to ten neutrophil functions were modeled using manual biocuration to determine each protein’s net effect on the respective neutrophil functions. Results: A total of 417 proteins were unique to asthmatic horses, 472 proteins were unique to control horses (p<0.05), and 114 proteins were common in both groups. Proteins whose biological activities are responsible for increasing neutrophil migration, chemotaxis, cell spreading, transmigration, and infiltration, which would collectively bring neutrophils to airways, were over-represented in the BALF of asthmatic relative to control horses. By contrast, proteins whose biological activities support neutrophil activation, adhesion, phagocytosis, respiratory burst, and apoptosis, which would collectively shorten neutrophil lifespan, were under-represented in BALF of asthmatic relative to control horses. Interaction networks generated using Ingenuity ® Pathways Analysis further support the results of our biocuration. Conclusion: Congruent with our hypothesis, the collective biological functions represented in differentially expressed proteins of BALF from horses with pasture-associated severe asthma support neutrophilic airway inflammation. This illustrates the utility of systems modeling to organize functional genomics data in a manner that characterizes complex molecular events associated with clinically relevant disease.

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Section: Discussionmentioning

confidence: 61%

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

Bright

Dittmar

Nanduri

et al. 2019

VMRR

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“…13 In this context, it is noted that matrikine is a cytokine exerting its effects in the extracellular matrix or basement membrane to modulate cellular function in different tissues and/or organs 69,70 ). In fact, tumstatin has now been used for the treatment of cancers, heart disease, and other pathogenesis wherein it exerts its effects as an angiogenesis inhibitor, 71 but also as a matrikine in the lung to lessen inflammatory response in lung tissue during chronic asthma-induced inflammation, 72 or serve as an anti-cancer agent, 69 and to protect ROS (reactive oxygen species, eg, H 2 O 2 )-induced apoptosis in cardiomyoblasts in the heart. 73 Collectively, the findings based on studies in other epithelia/tissues/organs thus support the notion that NC1-peptide is indeed a novel bioactive molecule capable of modulating a number of cellular processes to support cell and tissue homeostasis, such as spermatogenesis in the testis.…”

Section: Discussionmentioning

confidence: 99%

NC1‐peptide regulates spermatogenesis through changes in cytoskeletal organization mediated by EB1

Liu

et al. 2020

FASEB j.

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are contributed equally to the completion of this work.Abbreviations: +TIP, microtubule plus (+)-end tracking protein; AJ, adherens junction; aPKC, atypical protein kinase C; Arp3, actin-related protein 3; BM, basement membrane; BTB, blood-testis barrier; Crb3, Crumbs homolog-3; DAPI, 4', 6-diamidino-2-phenylindole; Dia1, Diaphanous-related formin-1; Dlg1, Discs large 1; Dvl3, Disheveled 3; EB1, end-binding protein 1; Eps8, epidermal growth factor receptor pathway substrate 8; ES, ectoplasmic specialization; Fzd3, Frizzled 3; F12/DMEM, Ham's F12 nutrient mixture/Dulbecco's modified Eagle's medium (1:1, vol/vol); GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GJ, gap junction; H&E, hematoxylin and eosin staining; IF, immunofluorescence microscopy; IgG, immunoglobulin; IP, immunoprecipitation; MAP1a, microtubule-associated protein 1a; MARK, microtubule affinity-regulatory kinase 4; MT, microtubule; mTOR, mammalian target of rapamycin; NC1 domain, non-collagenous domain 1; Pals1, protein associated with Lin-7 1; PatJ, Pals1-associated tight junction protein; Par6, partitioning-defective (Par) protein 6; rpS6, ribosomal protein S6; TJ, tight junction; ZO-1, zonula occludens-1. AbstractDuring the epithelial cycle of spermatogenesis, different sets of cellular events take place across the seminiferous epithelium in the testis. For instance, remodeling of the blood-testis barrier (BTB) that facilitates the transport of preleptotene spermatocytes across the immunological barrier and the release of sperms at spermiation take place at the opposite ends of the epithelium simultaneously at stage VIII of the epithelial cycle. These cellular events are tightly coordinated via locally produced regulatory biomolecules. Studies have shown that collagen α3 (IV) chains, a major constituent component of the basement membrane, release the non-collagenous (NC) 1 domain, a 28-kDa peptide, designated NC1-peptide, from the C-terminal region, via the action of MMP-9 (matrix metalloproteinase 9). NC1-peptide was found to be capable of inducing BTB remodeling and spermatid release across the epithelium. As such, the NC1-peptide is an endogenously produced biologically active peptide which coordinates these cellular events across the epithelium in stage VIII tubules. Herein, we used an animal model, wherein NC1-peptide cloned into the pCI-neo mammalian expression vector was overexpressed in the testis, to better understanding the molecular mechanism by which NC1-peptide regulated spermatogenic function. It was shown that NC1-peptide induced considerable downregulation on a number of cell polarity and planar cell polarity (PCP) proteins, and studies have shown these polarity and PCP proteins modulate spermatid polarity and adhesion via their effects on microtubule (MT) and F-actin cytoskeletal organization across the epithelium. More important, NC1-peptide exerted its effects by downregulating the expression of microtubule (MT) plus-end tracking protein (+TIP) called EB1 (end-binding protein 1). We cloned the full-length EB1 cDNA for its ov...

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“…In another study, Van der Velden et al identified an anti-angiogenic effect of tumstatin in a sheep model of asthma (286). Further investigations revealed a novel active region in Tumstatin (CP17), which significantly reduced neutrophil influx, mucus production in a mouse model of viral asthma exacerbation and reduced migrational speed and production of reactive oxygen species of neutrophils in vitro (287,288). While the matrikine tumstatin conveys protection from experimental features of asthma and asthma exacerbation, a collagen I derived matrikine (PGP, Acetylated-(Ac) PGP) has been shown to be a more potent inducer of neutrophil chemotaxis then IL-8 and is found to be increased in severe asthmatics, a group of patients prone to develop exacerbations (283,289).…”

Section: Airway Remodeling Is a Feature Of Human Rhinovirus Infectionmentioning

confidence: 99%

More Than Just a Barrier: The Immune Functions of the Airway Epithelium in Asthma Pathogenesis

et al. 2020

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Tumstatin fragment selectively inhibits neutrophil infiltration in experimental asthma exacerbation

Abstract: CP17 may serve as a potential precursor for drug development to combat overwhelming neutrophil inflammation.

Cited by 18 publications

References 60 publications

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

<p>Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation</p>

NC1‐peptide regulates spermatogenesis through changes in cytoskeletal organization mediated by EB1

More Than Just a Barrier: The Immune Functions of the Airway Epithelium in Asthma Pathogenesis

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