Intravenous adipose-derived mesenchymal stem cell therapy for the treatment of feline asthma: a pilot study

Objectives The aim of this study was to evaluate the feasibility and efficacy of serially administered adipose-derived mesenchymal stem cells (MSCs) in an experimental feline asthma model. Methods Allergic asthma was acutely induced with Bermuda grass allergen in six purpose-bred cats. Five intravenous infusions of allogeneic MSCs (n = 4; MSC-treated) or saline (n = 2; placebo-treated) were administered over the first 130 days after asthma induction. Infusions contained 2 × 106, 4 × 106, 4.7 × 106, 1 × 107 and 1 × 107 cryopreserved MSCs/cat. For thoracic imaging additional cats were enrolled as control groups: four untreated, experimentally asthmatic cats (combined with placebo-treated cats), and six healthy, non-asthmatic cats. Outcome measures included airway eosinophilia, pulmonary mechanics, thoracic computed tomography and several immunologic assays. Results Cats were assessed for 9 months after treatment. At early points, airway eosinophil percentage was not affected by MSC administration (post-treatment average of days 12, 26, 47, 108 and 133 in MSC-treated cats was 41 ± 15% and in placebo-treated cats it was 34 ± 16%). By month 9, eosinophil percentages in all MSC-treated cats decreased to normal reference intervals (MSC-treated 6%; placebo-treated 20%; normal <17%). Diminished airway hyper-responsiveness was noted in all MSC-treated compared with placebo-treated cats at day 133 (dose of methacholine to double baseline airway resistance: MSC-treated median 22.9 mg/ml [range 6.4–64.0]; individual placebo-treated cats 1.1 and 5.0 mg/ml). Lung attenuation (mean ± SEM MSC-treated −865 ± 12 Hounsfield units [HU]; untreated asthmatics −820 ± 11 HU; P = 0.004) and bronchial wall thickening scores (median [interquartile range] MSC-treated 0 [0–1.5]; untreated asthmatic 11.6 [7.3–27.3]; P = 0.010) were significantly reduced in MSC-treated vs untreated asthmatic cats, consistent with decreased airway remodeling at month 9. No clear immunologic mechanisms by which MSCs act were determined. Conclusions and relevance MSCs may have a delayed effect in reducing airway inflammation, airway hyper-responsiveness and remodeling in experimentally induced asthmatic cats. Results warrant additional investigation of MSC therapy for asthma in cats.

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Caveolin-1 scaffolding domain peptide prevents hyperoxia-induced airway remodeling in a neonatal mouse model

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00111.2018 ◽

2019 ◽

Vol 317 (1) ◽

pp. L99-L108 ◽

Cited By ~ 1

Author(s):

Elizabeth R. Vogel ◽

Logan J. Manlove ◽

Ine Kuipers ◽

Michael A. Thompson ◽

Yun-Hua Fang ◽

...

Keyword(s):

Mouse Model ◽

Airway Remodeling ◽

Supplemental Oxygen ◽

Neonatal Mouse ◽

Wall Thickening ◽

Airway Reactivity ◽

Caveolin 1 ◽

Airway Diseases ◽

Domain Peptide ◽

The Impact

Reactive airway diseases are significant sources of pulmonary morbidity in neonatal and pediatric patients. Supplemental oxygen exposure in premature infants contributes to airway diseases such as asthma and promotes development of airway remodeling, characterized by increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Decreased plasma membrane caveolin-1 (CAV1) expression has been implicated in airway disease and may contribute to airway remodeling and hyperreactivity. Here, we investigated the impact of clinically relevant moderate hyperoxia (50% O2) on airway remodeling and caveolar protein expression in a neonatal mouse model. Within 12 h of birth, litters of B6129SF2J mice were randomized to room air (RA) or 50% hyperoxia exposure for 7 days with or without caveolin-1 scaffolding domain peptide (CSD; caveolin-1 mimic; 10 µl, 0.25 mM daily via intraperitoneal injection) followed by 14 days of recovery in normoxia. Moderate hyperoxia significantly increased airway reactivity and decreased pulmonary compliance at 3 wk. Histologic assessment demonstrated airway wall thickening and increased ASM mass following hyperoxia. RNA from isolated ASM demonstrated significant decreases in CAV1 and cavin-1 in hyperoxia-exposed animals while cavin-3 was increased. Supplementation with intraperitoneal CSD mitigated both the physiologic and histologic changes observed with hyperoxia. Overall, these data show that moderate hyperoxia is detrimental to developing airway and may predispose to airway reactivity and remodeling. Loss of CAV1 is one mechanism through which hyperoxia produces these deleterious effects. Supplementation of CAV1 using CSD or similar analogs may represent a new therapeutic avenue for blunting hyperoxia-induced pulmonary damage in neonates.

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An Update for Mesenchymal Stem Cell Therapy in Lupus Nephritis

Kidney Diseases ◽

10.1159/000513741 ◽

2021 ◽

Vol 7 (2) ◽

pp. 79-89

Author(s):

Wenchao Li ◽

Weiwei Chen ◽

Lingyun Sun

Keyword(s):

Stem Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Mesangial Cells ◽

Treatment Options ◽

Novel Therapy ◽

Mesenchymal Stem Cell Therapy ◽

Allogeneic Mscs ◽

Senescent Phenotype ◽

Organ Manifestations

Background: Lupus nephritis (LN) is the most severe organ manifestations of systemic lupus erythematosus (SLE). Although increased knowledge of the disease pathogenesis has improved treatment options, outcomes have plateaued as current immunosuppressive therapies have failed to prevent disease relapse in more than half of treated patients. Thus, there is still an urgent need for novel therapy. Mesenchymal stem cells (MSCs) possess a potently immunosuppressive regulation on immune responses, and intravenous transplantation of MSCs ameliorates disease symptoms and has emerged as a potential beneficial therapy for LN. The objective of this review is to discuss the defective functions of MSCs in LN patients and the application of MSCs in the treatment of both LN animal models and patients. Summary: Bone marrow MSCs from SLE patients exhibit impaired capabilities of migration, differentiation, and immune regulation and display senescent phenotype. Allogeneic MSCs suppress autoimmunity and restore renal function in mouse models and patients with LN by inducing regulatory immune cells and suppressing Th1, Th17, T follicular helper cell, and B-cell responses. In addition, MSCs can home to the kidney and integrate into tubular cells and differentiate into mesangial cells. Key Messages: The efficacy of MSCs in the LN treatment remains to be confirmed, and future advances from stem cell science can be expected to pinpoint significant MSC subpopulations, as well as specific mechanisms of action, leading the way to the use of more potent stimulated or primed pretreated MSCs to treat LN.

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Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.1.140 ◽

1997 ◽

Vol 83 (1) ◽

pp. 140-147 ◽

Cited By ~ 54

Author(s):

Rodney K. Lambert ◽

Peter D. Paré

Keyword(s):

Smooth Muscle ◽

Shear Modulus ◽

Airway Remodeling ◽

Bronchial Hyperresponsiveness ◽

Lung Parenchyma ◽

Wall Thickening ◽

Forced Expiration ◽

Airway Wall ◽

Airway Narrowing ◽

Muscle Shortening

Lambert, Rodney K., and Peter D. Paré. Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness. J. Appl. Physiol.83(1): 140–147, 1997.—When airways narrow, either through the action of smooth muscle shortening or during forced expiration, the lung parenchyma is locally distorted and provides an increased peribronchial stress that resists the narrowing. Although this interdependence has been well studied, the quantitative significance of airway remodeling to interdependence has not been elucidated. We have used an improved computational model of the bronchial response to smooth muscle agonists to investigate the relationships between airway narrowing (as indicated by airway resistance), parenchymal shear modulus, adventitial thickening, and inner wall thickening at lung recoil pressures of 4, 5, and 8 cmH2O. We have found that, at low recoil pressures, decreases in parenchymal shear modulus have a significant effect that is comparable to that of moderate thickening of the airway wall. At higher lung recoil pressures, the effect is negligible.

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Small Airway Wall Thickening Assessed by Computerized Tomography Is Associated With Low Lung Function in Chinese Carbon Black Packers

Toxicological Sciences ◽

10.1093/toxsci/kfaa134 ◽

2020 ◽

Vol 178 (1) ◽

pp. 26-35

Author(s):

Xue Cao ◽

Li Lin ◽

Akshay Sood ◽

Qianli Ma ◽

Xiangyun Zhang ◽

...

Keyword(s):

Lung Function ◽

Carbon Black ◽

Elemental Carbon ◽

Airway Remodeling ◽

Forced Expiratory Volume ◽

Small Airway ◽

Wall Thickening ◽

Dependent Manner ◽

Airway Wall ◽

Wall Area

Abstract Nanoscale carbon black as virtually pure elemental carbon can deposit deep in the lungs and cause pulmonary injury. Airway remodeling assessed using computed tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural airway changes caused by carbon black exposure remain unknown. Wall and lumen areas of sixth and ninth generations of airways in 4 lobes were quantified using end-inhalation CT scans in 58 current carbon black packers (CBPs) and 95 non-CBPs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response. Environmental monitoring and CCAM showed a much higher level of elemental carbon exposure in CBPs, which was associated with higher wall area and lower lumen area with no change in total airway area for either airway generation. This suggested small airway wall thickening is a major feature of airway remodeling in CBPs. When compared with wall or lumen areas, wall area percent (WA%) was not affected by subject characteristics or lobar location and had greater measurement reproducibility. The effect of carbon black exposure status on WA% did not differ by lobes. CCAM was associated with WA% in a dose-dependent manner. CBPs had lower FEV1 (forced expiratory volume in 1 s) than non-CBPs and mediation analysis identified that a large portion (41–72%) of the FEV1 reduction associated with carbon black exposure could be explained by WA%. Small airway wall thickening as a major imaging change detected by CT may underlie the pathology of lung function impairment caused by carbon black exposure.

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Incidental Cardiac Findings on Thoracic Imaging

Canadian Association of Radiologists Journal ◽

10.1016/j.carj.2012.08.004 ◽

2013 ◽

Vol 64 (4) ◽

pp. 325-332 ◽

Cited By ~ 2

Author(s):

Hong Kuan Kok ◽

Bryan Loo ◽

William C. Torreggiani ◽

Orla Buckley

Keyword(s):

Computed Tomography ◽

Clinical Importance ◽

Careful Evaluation ◽

Thoracic Imaging ◽

Surgical Practice ◽

Prosthetic Valves ◽

Thoracic Computed Tomography ◽

Great Vessels ◽

Implantable Pacemaker

The cardiac structures are well seen on nongated thoracic computed tomography studies in the investigation and follow-up of cardiopulmonary disease. A wide variety of findings can be incidentally picked up on careful evaluation of the pericardium, cardiac chambers, valves, and great vessels. Some of these findings may represent benign variants, whereas others may have more profound clinical importance. Furthermore, the expansion of interventional and surgical practice has led to the development and placement of new cardiac stents, implantable pacemaker devices, and prosthetic valves with which the practicing radiologist should be familiar. We present a collection of common incidental cardiac findings that can be readily identified on thoracic computed tomography studies and briefly discuss their clinical relevance.

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Chronic exposure to diesel exhaust may cause small airway wall thickening without lumen narrowing: a quantitative computerized tomography study in Chinese diesel engine testers

Particle and Fibre Toxicology ◽

10.1186/s12989-021-00406-1 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Hong Liu ◽

Jianyu Li ◽

Qianli Ma ◽

Jinglong Tang ◽

Menghui Jiang ◽

...

Keyword(s):

Diesel Engine ◽

Diesel Exhaust ◽

Airway Remodeling ◽

Small Airway ◽

Wall Thickening ◽

Particulate Matters ◽

Airway Wall ◽

Wall Area ◽

Lumen Narrowing ◽

Area Percent

Abstract Background Diesel exhaust (DE) is a major source of ultrafine particulate matters (PM) in ambient air and contaminates many occupational settings. Airway remodeling assessed using computerized tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural changes of small airways caused by chronic DE exposure is unknown. Wall and lumen areas of 6th and 9th generations of four candidate airways were quantified using end-inhalation CT scans in 78 diesel engine testers (DET) and 76 non-DETs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response relationship. Results Environmental monitoring and CCAM showed a much higher PM exposure in DETs, which was associated with higher wall area and wall area percent for 6th generation of airways. However, no reduction in lumen area was identified. No study subjects met spirometry diagnosis of airway obstruction. This suggested that small airway wall thickening without lumen narrowing may be an early feature of airway remodeling in DETs. The effect of DE exposure status on wall area percent did not differ by lobes or smoking status. Although the trend test was of borderline significance between categorized CCAM and wall area percent, subjects in the highest CCAM category has a 14% increase in wall area percent for the 6th generation of airways compared to subjects in the lowest category. The impact of DE exposure on FEV1 can be partially explained by the wall area percent with mediation effect size equal to 20%, Pperm = 0.028). Conclusions Small airway wall thickening without lumen narrowing may be an early image feature detected by CT and underlie the pathology of lung injury in DETs. The pattern of changes in small airway dimensions, i.e., thicker airway wall without lumen narrowing caused by occupational DE exposure was different to that (i.e., thicker airway wall with lumen narrowing) seen in our previous study of workers exposed to nano-scale carbon black aerosol, suggesting constituents other than carbon cores may contribute to such differences. Our study provides some imaging indications of the understanding of the pulmonary toxicity of combustion derived airborne particulate matters in humans.

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Eighteen Questions for the Better Understanding of RADS

Journal of Clinical Cases & Reports ◽

10.46619/joccr.2020.3-1071 ◽

2020 ◽

Vol 3 (4) ◽

pp. 126-138

Author(s):

M Brooks Stuart ◽

Keyword(s):

Airway Hyperresponsiveness ◽

Airway Remodeling ◽

Inhalation Exposure ◽

Regenerative Process ◽

Wall Thickening ◽

High Concentration ◽

Airway Injury ◽

Tissue Healing ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

RADS are typically associated with a solitary inhalation exposure to a very high concentration of an irritant gas, vapor, aerosol or fume. Evolution of asthma-like symptoms and airway hyperresponsiveness are consequences Prompt medical assistance is needed within the first 24 hours. The manuscript unveils suggested sequences of RADS’ pathogenesis. The airway injury causes sloughing off of damaged and dead airway cells. Putatively, escaping intracellular molecules, from dead and damaged cells, enter the extracellular space as damage-associated molecular patterns (DAMPs); they are also known as “alarmins.” The molecules promote an inflammatory response and orchestrate cellular repair and tissue healing. Different mediators and regulatory intermediaries, chemokines and cytokines, arachidonic acid products, soluble growth factors, prostaglandins, and matrix components take part in regenerative process. Lung macrophages provide clean-up and repair services: and, they impact airway hyperresponsiveness. Metalloproteinases and extracellular matrix improve the epithelial-tomesenchymal matrix. Airway wall thickening, subepithelial fibrosis, mucus metaplasia, myofibroblast hyperplasia, muscle cells hyperplasia and hypertrophy, and epithelial hypertrophy become features of the airway remodeling response.

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Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00230.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. L199-L206 ◽

Cited By ~ 38

Author(s):

Alaina J. Ammit ◽

Lyn M. Moir ◽

Brian G. Oliver ◽

J. Margaret Hughes ◽

Hatem Alkhouri ◽

...

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Airway Remodeling ◽

Tissue Growth ◽

Wall Thickening ◽

Matrix Deposition ◽

Membrane Bound ◽

Extracellular Matrix Deposition ◽

Airway Walls ◽

Specific Membrane

Increased levels of IL-6 are documented in asthma, but its contribution to the pathology is unknown. Asthma is characterized by airway wall thickening due to increased extracellular matrix deposition, inflammation, angiogenesis, and airway smooth muscle (ASM) mass. IL-6 binds to a specific membrane-bound receptor, IL-6 receptor-α (mIL-6Rα), and subsequently to the signaling protein gp130. Alternatively, IL-6 can bind to soluble IL-6 recpetor-α (sIL-6Rα) to stimulate membrane receptor-deficient cells, a process called trans-signaling. We discovered that primary human ASM cells do not express mIL-6Rα and, therefore, investigated the effect of IL-6 trans-signaling on the pro-remodeling phenotype of ASM. ASM required sIL-6Rα to activate signal transducer and activator 3, with no differences observed between cells from asthmatic subjects compared with controls. Further analysis revealed that IL-6 alone or with sIL-6Rα did not induce release of matrix-stimulating factors (including connective tissue growth factor, fibronectin, or integrins) and had no effect on mast cell adhesion to ASM or ASM proliferation. However, in the presence of sIL-6Rα, IL-6 increased eotaxin and VEGF release and may thereby contribute to local inflammation and vessel expansion in airway walls of asthmatic subjects. As levels of sIL-6Rα are increased in asthma, this demonstration of IL-6 trans-signaling in ASM has relevance to the development of airway remodeling.

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