Vascular protection by young circulating extracellular vesicles ameliorates aging-related pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal, aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA-approved antifibrotic treatments are unable to reverse established disease, highlighting the need for innovative therapeutic approaches targeting novel pathways and cell types. Mounting evidence, including our own, has recently highlighted the pathogenic role of aging-related endothelial abnormalities, including vascular inflammation and oxidative stress, in the progression of lung fibrosis, offering new therapeutic opportunities to block IPF progression.

Hyperoxia-induced senescence in fetal airway smooth muscle cells: role of mitochondrial reactive oxygen species and endoplasmic reticulum stress.

Premature infants are at higher risk for developing chronic lung diseases, especially following supplemental oxygen (hyperoxia) in early life. We previously demonstrated that moderate hyperoxia (<60% O) induces cellular senescence in fetal airway smooth muscle cells (fASM) and fibroblasts. However, the mechanisms underlying O-induced senescence are still under investigation.

Aging, brain-derived neurotrophic factor, and allergen-induced pulmonary responses in mice.

Asthma in the elderly is being recognized as more severe, resistant to standard therapies, and having greater morbidity. Therefore, it becomes important to understand the impact of aging-associated airway structure and functional changes toward pathogenesis of asthma in the elderly. Here, airway smooth muscle plays important roles in airway hyperreactivity and structural remodeling.

Effects of glial-derived neurotrophic factor on remodeling and mitochondrial function in human airway smooth muscle cells.

Airway smooth muscle (ASM) cells play important roles in airway remodeling of asthma. Our previous studies show that in vivo administration of glial-derived neurotrophic factor (GDNF) in mice induces thickening and collagen deposition in bronchial airways, whereas chelation of GDNF by GFRα1-Fc attenuates airway remodeling in the context of allergen exposure. To determine whether GDNF has direct effects on ASM, in this study, we examined GDNF in ASM cells from normal versus asthmatic humans.

Endoplasmic reticulum stress-induced senescence in human lung fibroblasts.

Loss of proteostasis and cellular senescence have been previously established as characteristics of aging; however, their interaction in the context of lung aging and potential contributions to aging-associated lung remodeling remains understudied. In this study, we aimed to characterize endoplasmic reticulum (ER) stress response, cellular senescence, and their interaction in relation to extracellular matrix (ECM) production in lung fibroblasts from young (25-45 yr) and old (>60 yr) humans. Fibroblasts from young and old patients without significant preexisting lung disease were exposed to vehicle, MG132, etoposide, or salubrinal.

Functional role of glial-derived neurotrophic factor in a mixed allergen murine model of asthma.

Our previous study showed that glial-derived neurotrophic factor (GDNF) expression is upregulated in asthmatic human lungs, and GDNF regulates calcium responses through its receptor GDNF family receptor α1 (GFRα1) and RET receptor in human airway smooth muscle (ASM) cells. In this study, we tested the hypothesis that airway GDNF contributes to airway hyperreactivity (AHR) and remodeling using a mixed allergen mouse model. Adult C57BL/6J mice were intranasally exposed to mixed allergens (ovalbumin, , , house dust mite) over 4 wk with concurrent exposure to recombinant GDNF, or extracellular GDNF chelator GFRα1-Fc.

Functional α7 nicotinic receptors in human airway smooth muscle increase intracellular calcium concentration and contractility in asthmatics.

Although nicotinic acetylcholine receptors (nAChRs) are commonly associated with neurons in the brain and periphery, recent data indicate that they are also expressed in non-neuronal tissues. We recently found the alpha7 (α7nAChR) subunit is highly expressed in human airway smooth muscle (hASM) with substantial increase in asthmatics, but their functionality remains unknown. We investigated the location and functional role of α7nAChRs in hASM cells from normal versus mild-moderate asthmatic patients.

Asthmatic lung fibroblasts promote type 2 immune responses endoplasmic reticulum stress response dependent thymic stromal lymphopoietin secretion.

Lung fibroblasts contribute to asthma pathology partly through modulation of the immune environment in the airway. Tumor necrosis factor-α (TNFα) expression is upregulated in asthmatic lungs. How asthmatic lung fibroblasts respond to TNFα stimulation and subsequently regulate immune responses is not well understood.

Aging increases senescence, calcium signaling, and extracellular matrix deposition in human airway smooth muscle.

Lung function declines as people age and their lungs become stiffer. With an increasing elderly population, understanding mechanisms that contribute to these structural and functional changes in the aging lung is important. Part of the aging process is characterized by thicker, more fibrotic airways, and senile emphysema caused by changes in lung parenchyma.

Glial-derived neurotrophic factor in human airway smooth muscle.

Airway smooth muscle (ASM) cells modulate the local airway milieu via production of inflammatory mediators and growth factors including classical neurotrophins, such as brain-derived neurotrophic factor (BDNF). The glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs) are nonclassical neurotrophins and their role in the airway is barely understood. The major GFLs, GDNF and Neurturin (NRTN) bind to GDNF family receptor (GFR) α1 and α2 respectively that pair with Ret receptor to accomplish signaling.

Neurotrophin Regulation and Signaling in Airway Smooth Muscle.

Structural and functional aspects of bronchial airways are key throughout life and play critical roles in diseases such as asthma. Asthma involves functional changes such as airway irritability and hyperreactivity, as well as structural changes such as enhanced cellular proliferation of airway smooth muscle (ASM), epithelium, and fibroblasts, and altered extracellular matrix (ECM) and fibrosis, all modulated by factors such as inflammation. There is now increasing recognition that disease maintenance following initial triggers involves a prominent role for resident nonimmune airway cells that secrete growth factors with pleiotropic autocrine and paracrine effects.