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1.
Respir Res ; 23(1): 183, 2022 Jul 13.
Article in English | MEDLINE | ID: mdl-35831901

ABSTRACT

BACKGROUND: Airway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction. This study aimed to elucidate the mechanism by which pulmonary pericytes accumulate in the airway wall in a model of chronic allergic airway inflammation. METHODS: Mice were subjected to a protocol of chronic airway inflammation driven by the common environmental aeroallergen house dust mite. Phenotypic changes to lung pericytes were assessed by flow cytometry and immunostaining, and the functional capacity of these cells was evaluated using in vitro migration assays. The molecular mechanisms driving these processes were targeted pharmacologically in vivo and in vitro. RESULTS: Pericytes demonstrated increased CXCR4 expression in response to chronic allergic inflammation and migrated more readily to its cognate chemokine, CXCL12. This increase in migratory capacity was accompanied by pericyte accumulation in the airway wall, increased smooth muscle thickness, and symptoms of respiratory distress. Pericyte uncoupling from pulmonary vessels and subsequent migration to the airway wall were abrogated following topical treatment with the CXCL12 neutraligand LIT-927. CONCLUSION: These results provide new insight into the role of the CXCL12/CXCR4 signaling axis in promoting pulmonary pericyte accumulation and airway remodeling and validate a novel target to address tissue remodeling associated with chronic inflammation.


Subject(s)
Asthma , Chemokine CXCL12/metabolism , Hypersensitivity , Respiration Disorders , Airway Remodeling , Animals , Disease Models, Animal , Hypersensitivity/metabolism , Inflammation/metabolism , Lung , Mice , Pericytes/metabolism , Respiration Disorders/metabolism
2.
mBio ; 11(6)2020 11 17.
Article in English | MEDLINE | ID: mdl-33203752

ABSTRACT

To cause infection, Staphylococcus aureus must withstand damage caused by host immune defenses. However, the mechanisms by which staphylococcal DNA is damaged and repaired during infection are poorly understood. Using a panel of transposon mutants, we identified the rexBA operon as being important for the survival of Staphylococcus aureus in whole human blood. Mutants lacking rexB were also attenuated for virulence in murine models of both systemic and skin infections. We then demonstrated that RexAB is a member of the AddAB family of helicase/nuclease complexes responsible for initiating the repair of DNA double-strand breaks. Using a fluorescent reporter system, we were able to show that neutrophils cause staphylococcal DNA double-strand breaks through reactive oxygen species (ROS) generated by the respiratory burst, which are repaired by RexAB, leading to the induction of the mutagenic SOS response. We found that RexAB homologues in Enterococcus faecalis and Streptococcus gordonii also promoted the survival of these pathogens in human blood, suggesting that DNA double-strand break repair is required for Gram-positive bacteria to survive in host tissues. Together, these data demonstrate that DNA is a target of host immune cells, leading to double-strand breaks, and that the repair of this damage by an AddAB-family enzyme enables the survival of Gram-positive pathogens during infection.IMPORTANCE To cause infection, bacteria must survive attack by the host immune system. For many bacteria, including the major human pathogen Staphylococcus aureus, the greatest threat is posed by neutrophils. These immune cells ingest the invading organisms and try to kill them with a cocktail of chemicals that includes reactive oxygen species (ROS). The ability of S. aureus to survive this attack is crucial for the progression of infection. However, it was not clear how the ROS damaged S. aureus and how the bacterium repaired this damage. In this work, we show that ROS cause breaks in the staphylococcal DNA, which must be repaired by a two-protein complex known as RexAB; otherwise, the bacterium is killed, and it cannot sustain infection. This provides information on the type of damage that neutrophils cause S. aureus and the mechanism by which this damage is repaired, enabling infection.


Subject(s)
DNA Repair , Exodeoxyribonucleases/metabolism , Host-Pathogen Interactions , Staphylococcal Infections/microbiology , Staphylococcus aureus/genetics , Animals , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , DNA Breaks, Double-Stranded , Exodeoxyribonucleases/genetics , Female , Humans , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Reactive Oxygen Species/metabolism , Respiratory Burst
3.
Pharmacol Ther ; 151: 107-20, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25827580

ABSTRACT

Regenerative medicine using mesenchymal stem cells for the purposes of tissue repair has garnered considerable public attention due to the potential of returning tissues and organs to a normal, healthy state after injury or damage has occurred. To achieve this, progenitor cells such as pericytes and bone marrow-derived mesenchymal stem cells can be delivered exogenously, mobilised and recruited from within the body or transplanted in the form organs and tissues grown in the laboratory from stem cells. In this review, we summarise the recent evidence supporting the use of endogenously mobilised stem cell populations to enhance tissue repair along with the use of mesenchymal stem cells and pericytes in the development of engineered tissues. Finally, we conclude with an overview of currently available therapeutic options to manipulate endogenous stem cells to promote tissue repair.


Subject(s)
Mesenchymal Stem Cells/physiology , Pericytes/physiology , Regeneration , Tissue Engineering , Animals , Cell Movement , Fibrosis/pathology , Fibrosis/therapy , Humans , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/drug effects , Neovascularization, Physiologic , Pericytes/drug effects , Pericytes/transplantation
4.
Am J Physiol Lung Cell Mol Physiol ; 308(7): L658-71, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25637607

ABSTRACT

Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRß, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRß inhibitor (CP-673451) to investigate the role of PDGFRß signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRß signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRß signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma.


Subject(s)
Airway Remodeling , Asthma/pathology , Pericytes/physiology , Airway Resistance , Animals , Asthma/physiopathology , Becaplermin , Benzimidazoles/pharmacology , Bronchi/immunology , Bronchi/metabolism , Bronchi/pathology , Chronic Disease , Disease Models, Animal , Elasticity , Female , Mice, Inbred C57BL , Muscle, Smooth/pathology , Proto-Oncogene Proteins c-sis/metabolism , Quinolines/pharmacology , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/metabolism
5.
Int Arch Allergy Immunol ; 164(3): 178-88, 2014.
Article in English | MEDLINE | ID: mdl-25034005

ABSTRACT

Pericytes are mesenchymal cells embedded within the abluminal surface of the endothelium of microvessels such as capillaries, pre-capillary arterioles, post-capillary and collecting venules, where they maintain microvascular homeostasis and participate in angiogenesis. In addition to their roles in supporting the vasculature and facilitating leukocyte extravasation, pericytes have been recently investigated as a subpopulation of mesenchymal stem cells (MSCs) due to their capacity to differentiate into numerous cell types including the classic MSC triad, i.e. osteocytes, chondrocytes and adipocytes. Other studies in models of fibrotic inflammatory disease of the lung have demonstrated a vital role of pericytes in myofibroblast activation, collagen deposition and microvascular remodelling, which are hallmark features of chronic lung diseases such as asthma, chronic obstructive pulmonary disorder, pulmonary fibrosis and pulmonary hypertension. Further studies into the mechanisms of the pericyte-to-myofibroblast transition and migration to fibrotic foci will hopefully clarify the role of these cells in chronic lung disease and confirm the importance of pericytes in human fibrotic pulmonary disease.


Subject(s)
Inflammation/immunology , Lung/immunology , Mesenchymal Stem Cells/immunology , Pericytes/immunology , Pulmonary Fibrosis/immunology , Asthma/pathology , Cell Differentiation/immunology , Humans , Hypertension, Pulmonary/pathology , Lung/pathology , Myofibroblasts/immunology , Neovascularization, Pathologic , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Fibrosis/pathology
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