Metabolomics screening identifies reducedL-carnitine to be associated with progressive emphysema

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, small airway remodelling and emphysema. Emphysema is the destruction of alveolar structures, leading to enlarged airspaces and reduced surface area impairing the ability for gaseous exchange. To further understand the pathological mechanisms underlying progressive emphysema, we used MS-based approaches to quantify the lung, bronchoalveolar lavage fluid (BALF) and serum metabolome during emphysema progression in the established murine porcine pancreatic elastase (PPE) model on days 28, 56 and 161, compared with PBS controls. Partial least squares (PLS) analysis revealed greater changes in the metabolome of lung followed by BALF rather than serum during emphysema progression. Furthermore, we demonstrate for the first time that emphysema progression is associated with a reduction in lung-specific L-carnitine, a metabolite critical for transporting long-chain fatty acids into the mitochondria for their subsequent β-oxidation. In vitro, stimulation of the alveolar epithelial type II (ATII)-like LA4 cell line with L-carnitine diminished apoptosis induced by both PPE and H2O2. Moreover, PPE-treated mice demonstrated impaired lung function compared with PBS-treated controls (lung compliance; 0.067±0.008 ml/cmH20 compared with 0.035±0.005 ml/cmH20, P<0.0001), which improved following supplementation with L-carnitine (0.051±0.006, P<0.01) and was associated with a reduction in apoptosis. In summary, our results provide a new insight into the role of L-carnitine and, importantly, suggest therapeutic avenues for COPD.

Metabolomic similarities between bronchoalveolar lavage fluid and plasma in humans and mice

“…Dietary supplementation of L-carnitine has also been shown to reverse renal oxidative stress and mitochondrial dysfunction in female BALB/c mice who were exposed to cigarette smoke 44 . In a recent study, L-carnitine decreased with emphysema progression in mice, and L-carnitine supplementation improved lung function and reduced apoptosis 13 . Two vitamin D3 metabolites were down-regulated in BALF but up-regulated in plasma.…”

“…Dysregulations of these metabolites have previously been reported in the BALF of mice 12 , rats 16 , and humans 17 in association with asthma, COPD 13 and/or acute respiratory distress syndrome (ARDS). The presence of these molecules in both BALF and plasma suggests that plasma could be used as a surrogate for BALF, thereby providing a non-invasive fluid to study these lung diseases.…”

“…Recently, the serum and BALF metabolome were examined during the progression of emphysema in a murine porcine pancreatic elastase model 13 . The authors found a significant relationship between lung-specific L-carnitine and lung function; lung function was restored upon supplementation with L-carnitine.…”

Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

“…It is possible that the release of mtDNA and damage associated molecular patterns (DAMPS) occur in ACOS and during its exacerbations. Of a panel of lung metabolites analyzed in a model of progressive mouse emphysema, levels of L-carnitine were most significantly reduced (Conlon et al, 2016). Carnitine being essential to long chain fatty acid transfer into mitochondria may contribute to mitochondrial dysfunction.…”

Metabolomic profiling in a Hedgehog Interacting Protein (Hhip) murine model of chronic obstructive pulmonary disease

“…Interestingly, increased plasma levels of C6 and C8 carnitine are characteristic of medium chain acyl-CoA dehydrogenase deficiency (MCAD; OMIM 201450), an autosomal recessive disorder characterized by an intolerance to fasting 15, 16 . Although the functional impact of decreased levels of plasma C6 and C8 carnitine is not known, decreased levels of L-carnitine in lung tissues were recently reported in a porcine pancreatic elastase murine model of emphysema 17 .…”