Abstract
The effects of airway inflammation on airway smooth muscle (ASM) are mediated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα). In this review article, we will provide a unifying hypothesis for a homeostatic response to airway inflammation that mitigates oxidative stress and thereby provides resilience to ASM. Previous studies have shown that acute exposure to TNFα increases ASM force generation in response to muscarinic stimulation (hyper-reactivity) resulting in increased ATP consumption and increased tension cost. To meet this increased energetic demand, mitochondrial O2 consumption and oxidative phosphorylation increases but at the cost of increased reactive oxygen species (ROS) production (oxidative stress). TNFα-induced oxidative stress results in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and mitochondria of ASM. In the ER, TNFα selectively phosphorylates inositol-requiring enzyme 1 alpha (pIRE1α) triggering downstream splicing of the transcription factor X-box binding protein 1 (XBP1s); thus, activating the pIRE1α/XBP1s ER stress pathway. Protein unfolding in mitochondria also triggers an unfolded protein response (mtUPR). In our conceptual framework, we hypothesize that activation of these pathways is homeostatically directed towards mitochondrial remodeling via an increase in peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) expression, which in turn triggers: (1) mitochondrial fragmentation (increased dynamin-related protein-1 (Drp1) and reduced mitofusin-2 (Mfn2) expression) and mitophagy (activation of the Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin mitophagy pathway) to improve mitochondrial quality; (2) reduced Mfn2 also results in a disruption of mitochondrial tethering to the ER and reduced mitochondrial Ca2+ influx; and (3) mitochondrial biogenesis and increased mitochondrial volume density. The homeostatic remodeling of mitochondria results in more efficient O2 consumption and oxidative phosphorylation and reduced ROS formation by individual mitochondrion, while still meeting the increased ATP demand. Thus, the energetic load of hyper-reactivity is shared across the mitochondrial pool within ASM cells.
Highlights
Airway inflammation underlies a number of pathological conditions such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, COVID-19 and various cough syndromes
In a recently published lished study, we demonstrated that TNFα selectively activates the inositol-requiring enstudy, we demonstrated that TNFα selectively activates the inositol-requiring enzyme 1 zyme 1 alpha mediated endoplasmic reticulum (ER) stress pathway in human airway smooth muscle (ASM), which induces alteralpha mediated ER stress pathway in human ASM, which induces alternative native splicing of mRNA for the transcription factor X-box binding protein 1 (XBP1s) [3]
In human ASM, we previously showed that TNFα exposure and increased reactive oxygen species (ROS) formation lead to an accumulation of unfolded proteins in the ER lumen, which trigger a homeostatic signaling cascade to restore normal function (i.e., ER stress response) [3]
Summary
Airway inflammation underlies a number of pathological conditions such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, COVID-19 and various cough syndromes. The canonical mt UPR pathway involves crosstalk between mitochondria and the nucleus via the recruitment of transcription factors such as CHOP, ATF4, and activating transcription factor 5 (ATF5) Acting together, these chaperones and transcription factors promote an integrated stress response (ISR) [27,28,29], resulting in the production of various antioxidants, chaperones and proteases to reduce stress and protein damage inside the mitochondrial matrix [5,6]. These chaperones and transcription factors promote an integrated stress response (ISR) [27,28,29], resulting in the production of various antioxidants, chaperones and proteases to reduce stress and protein damage inside the mitochondrial matrix [5,6] This ISR is coordinated with an ER stress response by phosphorylation of eIF2α as a downstream effector of the PERK/eIF2α ER stress pathway, which can be activated by increased ROS, amino acid depletion and ER dysfunction [26,30].
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