Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by different patterns of airway remodeling, which all include an increased mass of bronchial smooth muscle (BSM). A remaining major question concerns the mechanisms underlying such a remodeling of BSM. Because mitochondria play a major role in both cell proliferation and apoptosis, we hypothesized that mitochondrial activation in BSM could play a role in this remodeling. We describe that both the mitochondrial mass and oxygen consumption were higher in the BSM from asthmatic subjects than in that from both COPD and controls. This feature, which is specific to asthma, was related to an enhanced mitochondrial biogenesis through up-regulation of peroxisome proliferator-activated receptor γ coactivator (PGC)–1α, nuclear respiratory factor-1, and mitochondrial transcription factor A. The priming event of such activation was an alteration in BSM calcium homeostasis. BSM cell apoptosis was not different in the three groups of subjects. Asthmatic BSM was, however, characterized by increased cell growth and proliferation. Both characteristics were completely abrogated in mitochondria-deficient asthmatic BSM cells. Conversely, in both COPD and control BSM cells, induction of mitochondrial biogenesis reproduced these characteristics. Thus, BSM in asthmatic patients is characterized by an altered calcium homeostasis that increases mitochondrial biogenesis, which, in turn, enhances cell proliferation, leading to airway remodeling.

Magnesium and calcium in exhaled breath condensate of children with asthma and gastroesophageal reflux disease

“…Determination of plasma magnesium did not prove useful in the follow-up of asthma exacerbation (15,(27)(28)(29)(30)(31). On the other hand, determination of magnesium concentration in various cell types pointed to magnesium redistribution but failed to identify the cell type best indicating the body magnesium status (32,33).…”

“…Besides inflammation, bronchoconstriction is a major characteristic of asthma (28), whereby calcium (Ca 21 ) acts as an important activator of airway smooth muscle contractions (29), being also involved in airway remodeling (30). Magnesium as a physiologic calcium antagonist (5) has a role in smooth muscle relaxation, and magnesium deficiency is associated with increased smooth muscle contractility, including bronchial smooth muscle (15).…”

Mitochondria in lung disease

“…ALI and ARDS result from the inflammatory response of the lung to both direct and indirect insults and are characterized by severe hypoxemia, hypercapnia, diffuse infiltration visible in the chest x-ray, and a substantial reduction in pulmonary compliance (45). Mitochondrial biogenesis is increased in bronchial smooth muscle remodeling in asthma (46) and in lung cancer; however, in lung cancer, it is unclear whether these alterations contribute to tumorigenesis or are a consequence of carcinogenesis (47). In contrast, loss of mitochondrial biogenesis is associated with COPD, which may be associated with a significantly lower body mass index and lower muscle mass (ref.…”

Airway Smooth Muscle: Is There a Phenotype Associated with Asthma?

“…Multiple stimuli that modulate inflammation, proliferation and asthma also activate NF-κB transcription factors, and disruption of NF-κB activation through expression of a super-repressor form of IKB substantially impairs proliferation (Brar et al, 2002;Clarke et al, 2009;Damera et al, 2009b). Explaining increased mitochondrial mass and oxygen consumption in asthmatic ASM, Trian et al show differences in mitochondrial biogenesis and expression of transcription factors such as peroxisome proliferator-activated receptor co-activator (PGC)-1 , nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (mtTFA) in ASM derived from asthma, COPD and normal populations (Trian et al, 2007).…”