Respiratory protease/antiprotease balance determines susceptibility to viral infection and can be modified by nutritional antioxidants

Meyer, Mark J.; Jaspers, Ilona

doi:10.1152/ajplung.00028.2015

Cited by 58 publications

(66 citation statements)

References 186 publications

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“…However, a growing body of research has uncovered their involvement in a series of intracellular and extracellular regulatory processes, including tissue remodelling, mucin expression, bacterial killing and neutrophil chemotaxis [29]. With respect to the lung, proteases are secreted from bronchial epithelial cells and are also expressed in monocyte, lymphocyte and granulocyte cell lineages, especially in neutrophils [30]. Proteases cleave extracellular matrix (ECM) proteins, antimicrobial peptides (AMPs) and antiproteases, and they have implications in the immune response to infection.…”

Section: Proteasesmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

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Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.

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Section: Proteasesmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

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“…A loss or functional impairment of Tregs, for example by respiratory viruses, could predispose them to the development of lung-restricted immunity. Respiratory viral infections, indeed, are common in patients with underlying lung disease (62, 63). …”

Section: Discussionmentioning

confidence: 99%

Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity

Chiu

Fernández

Subramanian

et al. 2016

The Journal of Immunology

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Over one-third of patients with chronic lung disease undergoing lung transplantation have pre-existing antibodies against lung-restricted self-antigens, collagen type V (ColV) and k-alpha1 tubulin (KAT). These antibodies can also develop de novo following lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Since these self-antigens are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4+CD25+Foxp3+ T cells (Tregs), the key mediators of self-tolerance. Therefore, we hypothesized that lung-tissue injury can lead to lung-restricted immunity if it occurs in a setting when Tregs are impaired. We found that human lung recipients who suffer respiratory viral infections experienced a decrease in peripheral Tregs. Pre-existing lung allograft injury from donor-directed antibodies or gastroesophageal reflux led to new ColV and KAT antibodies following respiratory viral infection. Similarly, murine parainfluenza (Sendai) respiratory viral infection caused a decrease in Tregs. Intratracheal instillation of anti-MHC class-I antibodies, but not isotype control, followed by murine Sendai virus (SdV) infection led to development of antibodies against ColV and KAT, but not collagen II (ColII), a cartilaginous protein. This was associated with expansion of IFN-γ producing CD4+ T cells specific to ColV and KAT, but not ColII. Intratracheal anti-MHC class-I antibodies or hydrochloric acid in Foxp3-DTR mice induced ColV and KAT, but not ColII, immunity, only if Tregs were depleted using diphtheria toxin. We conclude that tissue injury combined with loss of Tregs can lead to lung-tissue restricted immunity.

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“…Respiratory anti-proteases comprise serine protease inhibitors (serpins), tissue inhibitors of metalloproteinase, trappin-2/elafin, and secretory leukoprotease inhibitor (SLPI) [61]. These inhibitors not only neutralise protease activity, but also display anti-microbial and immune modulatory actions, which are highly relevant in chronic lung pathologies, such as in cystic fibrosis and COPD, where there is a combination of infection and exacerbated host responses [62,63]. The clinical importance of protease inhibition is supported by studies demonstrating that inhibitor deficiencies result in structural lung damage.…”

Section: Proteases and Natural Serine Protease Inhibitors: The Dangermentioning

confidence: 99%

Protean proteases: at the cutting edge of lung diseases

et al. 2017

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Proteases were traditionally viewed as mere protein-degrading enzymes with a very restricted spectrum of substrates. A major expansion in protease research has uncovered a variety of novel substrates, and it is now evident that proteases are critical pleiotropic actors orchestrating pathophysiological processes. Recent findings evidenced that the net proteolytic activity also relies upon interconnections between different protease and protease inhibitor families in the protease web.In this review, we provide an overview of these novel concepts with a particular focus on pulmonary pathophysiology. We describe the emerging roles of several protease families including cysteine and serine proteases.The complexity of the protease web is exemplified in the light of multidimensional regulation of serine protease activity by matrix metalloproteases through cognate serine protease inhibitor processing. Finally, we will highlight how deregulated protease activity during pulmonary pathogenesis may be exploited for diagnosis/prognosis purposes, and utilised as a therapeutic tool using nanotechnologies.Considering proteases as part of an integrative biology perspective may pave the way for the development of new therapeutic targets to treat pulmonary diseases related to intrinsic protease deregulation.

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Respiratory protease/antiprotease balance determines susceptibility to viral infection and can be modified by nutritional antioxidants

Cited by 58 publications

References 186 publications

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity

Protean proteases: at the cutting edge of lung diseases

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