Lactic Acid Metabolism May Be ‘Important’ Therapy Target in IPF
Alterations in lactic acid metabolism — part of the process that allows the body to produce energy in the absence of oxygen — were found in lung tissues collected from patients with idiopathic pulmonary fibrosis (IPF), a recent study reported.
These findings suggest that lactic acid metabolism may be an “important” therapy target for IPF treatment, according to the researchers.
The scientists said their results confirmed their hypothesis that “altered lactate metabolism in [certain cell types] plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment.”
Thus, lactic acid metabolism “may be a novel and important target for therapeutic treatment,” they wrote.
The study, “Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue,” was published in the journal Respiratory Research.
IPF is characterized by the progressive and extensive formation of fibrous scar tissue in the lungs. Scarring in IPF occurs due to the uncontrolled activation of fibroblasts — the most common type of connective tissue cell that produces a protein called collagen.
Despite the well-defined role of fibroblasts in IPF progression, growing evidence indicates that cells lining the tiny air sacs in the lungs — called alveolar type II epithelial cells or AEC2s — which play a key role in gas exchange, are the initial site of damage that drives the disease.
Studies have shown that injured AEC2 cells produce pro-fibrotic signals that stimulate the activation of fibroblasts. As such, AEC2 cells have been identified as a potentially effective therapeutic target to treat IPF.
Lactic acid is a chemical byproduct of a metabolic process that allows cells to produce energy — by breaking down glucose (blood sugar) — in the absence of oxygen. When exercising, particularly under strenuous conditions, lactic acid builds up in muscle tissues, as cells start using this alternative metabolic cascade to produce energy faster.
The chemical byproduct is then transported from muscles to the liver, where it is converted back to glucose, which is then used as fuel for further energy generation.
In the lung tissues of IPF patients, lactic acid has been found to be around three times higher than it is in the tissues of healthy individuals, consistent with alterations in cellular metabolism. Furthermore, the expression (production) of the enzyme that generates lactic acid — lactate dehydrogenase (LDH) — is enhanced in IPF.
A team of researchers at the Medical University of South Carolina had reported that healthy AEC2 cells preferentially use lactic acid as a metabolic substrate for energy production.
Now, the same team of scientists examined and compared the metabolic profile of AEC2s in lung tissues from IPF patients and individuals who did not have lung fibrosis to determine whether lactic acid metabolism is affected in IPF AEC2s.
Their hypothesis was that altered lactate metabolism in AEC2 affects IPF development and progression by impacting critical cellular and molecular interactions. To test this, the team measured oxygen-consumption rates, or OCR, and proton-production rates, known as PPR, in AEC2 cells isolated from three IPF and three healthy (control) lung tissue samples.
OCR measures oxidative energy metabolism, in which glucose is used as fuel for energy generation in the presence of oxygen. In contrast, PPR is a measure of glycolysis — a different method of producing energy from glucose that generates lactic acid and is independent of oxygen.
Tests showed that AEC2 cells from IPF lung samples had lower OCR, but similar PPR compared with controls, “indicating enhanced glycolytic vs. oxidative metabolism.”
Based on these findings, the team investigated whether this metabolic shift in IPF AEC2s was associated with forms of the LDH enzyme that favor a glycolytic metabolism.
The LDH enzyme is composed of four subunits, made with combinations of two different proteins, LDHA and LDHB. The LDH forms — LDH4 and LDH5 — have a higher LDHA to LDHB ratio, and favor a glycolytic metabolism.
Analysis showed that, compared with control samples, LDH4 and LDH5 combined represented more than 60% of the total active LDH enzyme pool in IPF AEC2s. In contrast, AEC2s from non-fibrotic lungs expressed more LDH2 and LDH3 forms, containing more LDHB.
Consistent with these results, the ratio of LDHA to LDHB subunit expression was significantly higher in AEC2s from IPF lungs than controls.
Finally, researchers designed experiments to confirm the expression of these LDH forms found in IPF lungs was associated with changes in energy metabolism. Here, AEC2 cells purified from an IPF lung tissue sample were subjected to a treatment called siRNA-mediated knockdown that selectively suppressed the expression of LDHA to lower the LDHA:LDHB ratio.
Compared with a siRNA control, cells in which LDHA expression was blocked with an LDHA siRNA showed a 66% reduction in the expression of LDHA. Consequently, this changed the relative proportions of LDH enzyme forms, increasing LDH2 and LDH3 forms (containing more LDHB subunits) and reducing LDH4 and LDH5 forms.
Not only did IPF AEC2 cells with suppressed LDHA expression resemble AEC2s from non-fibrotic lungs, but they also had significantly higher OCR, similar to non-fibrotic AEC2 cells. Overall, less LDHA correlated with a lower PPR/OCR ratio in the IPF AEC2s compared with siRNA controls.
“Thus, manipulation of LDH [form] expression per se in IPF AEC2s drove a metabolic shift to AEC2s resembling those from non-fibrotic lungs,” the team wrote.
“The results of this study are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment,” the researchers concluded.
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