ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

Acute and chronic lung inflammation is driven and controlled by several endogenous mediators that undergo proteolytic conversion from surface-expressed proteins to soluble variants by a disintegrin and metalloproteinase (ADAM)-family members. TNF and epidermal growth factor receptor ligands are just some of the many substrates by which these proteases regulate inflammatory or regenerative processes in the lung. ADAM10 and ADAM17 are the most prominent members of this protease family. They are constitutively expressed in most lung cells and, as recent research has shown, are the pivotal shedding enzymes mediating acute lung inflammation in a cell-specific manner. ADAM17 promotes endothelial and epithelial permeability, transendothelial leukocyte migration, and inflammatory mediator production by smooth muscle and epithelial cells. ADAM10 is critical for leukocyte migration and alveolar leukocyte recruitment. ADAM10 also promotes allergic asthma by driving B cell responses. Additionally, ADAM10 acts as a receptor for Staphylococcus aureus ( S. aureus) α-toxin and is crucial for bacterial virulence. ADAM8, ADAM9, ADAM15, and ADAM33 are upregulated during acute or chronic lung inflammation, and recent functional or genetic analyses have linked them to disease development. Pharmacological inhibitors that allow us to locally or systemically target and differentiate ADAM-family members in the lung suppress acute and asthmatic inflammatory responses and S. aureus virulence. These promising results encourage further research to develop therapeutic strategies based on selected ADAMs. These studies need also to address the role of the ADAMs in repair and regeneration in the lung to identify further therapeutic opportunities and possible side effects.

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L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.

Journal of Experimental Medicine ◽

10.1084/jem.181.6.2259 ◽

1995 ◽

Vol 181 (6) ◽

pp. 2259-2264 ◽

Cited By ~ 286

Author(s):

T F Tedder ◽

D A Steeber ◽

P Pizcueta

Keyword(s):

Cell Surface ◽

Inflammatory Responses ◽

Significant Inhibition ◽

Leukocyte Migration ◽

Contact Hypersensitivity ◽

Delayed Type Hypersensitivity ◽

Surface Adhesion ◽

Wild Type ◽

A Cell ◽

Deficient Mice

L-selectin, a cell surface adhesion molecule that is expressed by most leukocytes, mediates leukocyte rolling along vascular endothelium at sites of inflammation. The contribution of L-selectin to leukocyte migration in models of chronic inflammation was assessed by using mice that lack cell surface L-selectin expression. Significant inhibition of neutrophil (56-62%), lymphocyte (70-75%), and monocyte (72-78%) migration into an inflamed peritoneum was observed 24 and 48 h after administration of thioglycollate, an inflammatory stimulus. L-selectin-deficient mice were also significantly impaired in delayed-type hypersensitivity reactions. Footpad swelling in response to sheep red blood cell challenge was reduced 75% in L-selectin-deficient mice compared with wild-type mice. Ear swelling in a model of contact hypersensitivity induced by oxazolone challenge was also reduced by 69% compared to wild-type mice. Consistent with L-selectin-mediating leukocyte migration into diverse vascular beds during inflammation, L-selectin-deficient mice were significantly resistant to death resulting from lipopolysaccharide (LPS)-induced toxic shock. LPS administration resulted in a 90% mortality rate in control mice after 24 h, while there was a 90% survival rate in L-selectin-deficient mice. These results demonstrate that L-selectin plays a prominent role in leukocyte homing to nonlymphoid tissues during inflammation and that blocking this process can be beneficial during pathological inflammatory responses.

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Gender Differences in Low-Molecular-Mass-Induced Acute Lung Inflammation in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22010419 ◽

2021 ◽

Vol 22 (1) ◽

pp. 419

Author(s):

Yifang Xie ◽

Dehui Xie ◽

Bin Li ◽

Hang Zhao

Keyword(s):

Gender Differences ◽

Sex Differences ◽

Molecular Mass ◽

Lung Inflammation ◽

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Ovarian Hormones ◽

Male Mice ◽

Acute Lung Inflammation ◽

17Β Estradiol

Gender differences in pulmonary inflammation have been well documented. Although low molecular mass hyaluronan (LMMHA) is known to trigger pulmonary lung inflammation, sex differences in susceptibility to LMMHA are still unknown. In this study, we test the hypothesis that mice may display sex-specific differences after LMMHA administration. After LMMHA administration, male mice have higher neutrophil, cytokine, and chemokine counts compared to that of their female counterparts. Additionally, Ovariectomized (OVX) mice show greater LMMHA-induced inflammation compared to that of mice with intact ovaries. Injections of OVX mice with 17β-estradiol can decrease inflammatory responses in the OVX mice. These results show that ovarian hormones regulate LMMHA induced lung inflammation.

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Myeloid cells control termination of lung inflammation through the NF-κB pathway

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90485.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. L320-L327 ◽

Cited By ~ 27

Author(s):

Wei Han ◽

Myungsoo Joo ◽

M. Brett Everhart ◽

John W. Christman ◽

Fiona E. Yull ◽

...

Keyword(s):

Bone Marrow ◽

Lung Inflammation ◽

Inflammatory Responses ◽

Fetal Liver ◽

Myeloid Cells ◽

A549 Cells ◽

Systemic Infection ◽

Wild Type ◽

Acute Lung Inflammation ◽

Bone Marrow Chimeras

Although acute lung inflammation in response to local or systemic infection involves myeloid and nonmyeloid cells, the interplay between different cell types remains poorly defined. Since NF-κB is a key transcription factor for innate immunity, we investigated whether dysregulated NF-κB activation in myeloid cells impacts inflammatory signaling in nonmyeloid cells and generation of neutrophilic lung inflammation in response to systemic endotoxemia. We generated bone marrow chimeras by fetal liver transplantation of cells deficient in IκBα or p50 into lethally irradiated NF-κB reporter transgenic mice. No differences were apparent between bone marrow chimeras in the absence of an inflammatory stimulus; however, following intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS), IκBα- or p50-deficient bone marrow chimeras showed increased NF-κB activation in nonhematopoietic cells, exaggerated neutrophilic inflammation, and higher mortality compared with untransplanted reporter mice and wild-type bone marrow chimeras. Primary bone marrow-derived macrophages (BMDM) from IκBα−/−or p50−/−exhibited increased NF-κB activation and macrophage inflammatory protein-2 production after LPS treatment compared with wild-type cells, and coculture of BMDM with lung epithelial (A549) cells resulted in increased NF-κB activation in A549 cells and excess IL-8 production by these epithelial cells. These studies indicate an important role for inhibitory members of the NF-κB family acting specifically within myeloid cells to limit inflammatory responses in the lungs.

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Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane Proteins

10.26434/chemrxiv.7927061.v1 ◽

2019 ◽

Cited By ~ 2

Author(s):

Steven Banik ◽

Kayvon Pedram ◽

Simon Wisnovsky ◽

Nicholas Riley ◽

Carolyn Bertozzi

Keyword(s):

Epidermal Growth Factor Receptor ◽

Membrane Proteins ◽

Growth Factor Receptor ◽

Basic Research ◽

Biochemical Pathway ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

A Cell ◽

Epidermal Growth ◽

Powerful Strategy

<p>Targeted protein degradation is a powerful strategy to address the canonically undruggable proteome. However, current technologies are limited to targets with cytosolically-accessible and ligandable domains. Here, we designed and synthesized conjugates capable of binding both a cell surface lysosome targeting receptor and the extracellular domain of a target protein. These lysosome targeting chimeras (LYTACs) consist of an antibody fused to agonist glycopeptide ligands for the cation-independent mannose-6-phosphate receptor (CI-M6PR). LYTACs enabled a CRISPRi knockdown screen revealing the biochemical pathway for CI-M6PR-mediated cargo internalization. We demonstrated that LYTACs mediate efficient degradation of Apolipoprotein-E4, epidermal growth factor receptor (EGFR), CD71, and programmed death-ligand 1 (PD-L1). LYTACs represent a modular strategy for directing secreted and membrane proteins for degradation in the context of both basic research and therapy. <b></b></p>

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Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽

10.3390/nano11010180 ◽

2021 ◽

Vol 11 (1) ◽

pp. 180

Author(s):

Maud Weiss ◽

Jiahui Fan ◽

Mickaël Claudel ◽

Luc Lebeau ◽

Françoise Pons ◽

...

Keyword(s):

Carbon Dots ◽

Lung Inflammation ◽

Adverse Outcome ◽

Cellular Responses ◽

Target Cells ◽

Inflammasome Activation ◽

Adverse Outcome Pathway ◽

Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

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Administration route governs the therapeutic efficacy, biodistribution and macrophage targeting of anti-inflammatory nanoparticles in the lung

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00803-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lu Wang ◽

Yafei Rao ◽

Xiali Liu ◽

Liya Sun ◽

Jiameng Gong ◽

...

Keyword(s):

Therapeutic Efficacy ◽

Lung Inflammation ◽

Respiratory Diseases ◽

Inflammatory Responses ◽

The Other ◽

Target Cells ◽

Administration Route ◽

Toll Like Receptor ◽

Administration Routes ◽

Anti Inflammatory

Abstract Background Uncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined. Results In this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not. Conclusion The i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects.

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Biomedical Uses of Sulfobetaine-Based Zwitterionic Materials

Organic Materials ◽

10.1055/s-0040-1721741 ◽

2020 ◽

Vol 02 (04) ◽

pp. 342-357

Author(s):

Francesco Zaccarian ◽

Matthew B. Baker ◽

Matthew J. Webber

Keyword(s):

Biomedical Applications ◽

Foreign Body Reaction ◽

Inflammatory Responses ◽

Cellular Adhesion ◽

Review Of The Literature ◽

Future Prospects ◽

Protein Fouling ◽

Biomedical Device ◽

The Many ◽

Hydrophilic Coatings

Protein fouling can render a biomedical device dysfunctional, and also serves to nucleate the foreign body reaction to an implanted material. Hydrophilic coatings have emerged as a commonly applied route to combat interface-mediated complications and promote device longevity and limited inflammatory response. While polyethylene glycol has received a majority of the attention in this regard, coatings based on zwitterionic moieties have been more recently explored. Sulfobetaines in particular constitute one such class of zwitterions explored for use in mitigating surface fouling, and have been shown to reduce protein adsorption, limit cellular adhesion, and promote increased functional lifetimes and limited inflammatory responses when applied to implanted materials and devices. Here, we present a focused review of the literature surrounding sulfobetaine, beginning with an understanding of its chemistry and the methods by which it is applied to the surface of a biomedical device in molecular and polymeric forms, and then advancing to the many early demonstrations of function in a variety of biomedical applications. Finally, we provide some insights into the benefits and challenges presented by its use, as well as some outlook on the future prospects for using this material to improve biomedical device practice by addressing interface-mediated complications.

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