Lactate regulation in high-altitude hypoxic adaptation attenuates LPS-Induced acute lung injury: links to glucose metabolism and anti-inflammatory therapeutic potential

Dear editors,

We read with great interest the review by Tchatat et al. in Critical Care [1], which emphasizes lactate—particularly hypertonic sodium lactate (HSL)—as more than a marker of illness severity. The authors summarize evidence that HSL can improve hemodynamics, tissue perfusion and microcirculation, dampen inflammation, and support organ function in sepsis, acute heart failure, and brain injury. This is consistent with previous reviews and also reflects the latest advances in understanding the interplay between lactate and sepsis [2]. Collectively, these findings argue that lactate should not be viewed solely as a metabolic byproduct; it may also serve as an energy substrate and an organ-protective mediator in critical illness.

This viewpoint is consistent with our previous clinical findings [3]. Clinically, in patients undergoing hepatectomy, we observed that those who had long-term residence at high altitude exhibited more stable perioperative blood glucose and lactate levels, and both the incidence and severity of postoperative pulmonary complications were reduced in high-altitude residents compared with low-altitude patients.These observations prompted us to explore whether lactate-related metabolic adaptations might contribute to protection against acute lung injury (ALI).

To verify this effect, we established a rat model of high-altitude hypoxic preconditioning induced by a hypobaric chamber (high-altitude hypoxic preconditioning, HAHP), specifically, six-week-old male Sprague–Dawley rats (n = 24) were randomly divided into hypobaric hypoxia and normoxia groups, housed for four weeks, injected intraperitoneally with lipopolysaccharide (LPS, 10 mg/kg), and euthanized 6 h later for sample collection. After LPS challenge, the high-altitude LPS (HL) group showed a modest decrease in blood glucose, while lactate increased markedly (Fig. 1A–B). Consistently, pulmonary edema was improved in HL, as shown by a significantly lower lung dry-to-wet weight ratio (D/W) (p < 0.0001) (Fig. 1C). Histopathology indicated substantially attenuated lung injury in the HL group, with better preserved alveolar architecture; in contrast, the low-altitude LPS (CL) group exhibited prominent neutrophil infiltration, thickened alveolar septa, structural destruction, and congestion (Fig. 1D).

Fig. 1.

Lactate regulation in high-altitude hypoxic adaptation attenuates LPS-induced acute lung injury and links to glucose metabolism and anti-inflammatory potentia. (A) Blood glucose measured by arterial blood gas analysis. (B) Blood lactate measured by arterial blood gas analysis. (C) Lung dry-to-wet weight ratio (D/W). (D) Representative H&E-stained lung sections. (E) Representative immunofluorescence images showing CD206, CD86, and HLA-DR expression in lung tissue; scale bar = 50 μm. (F-H) Quantification of relative fluorescence intensity of CD206, CD86, and HLA-DR. (I) SOD levels measured by ELISA. (J) TNF-α levels measured by ELISA. (K-L) Arterial blood gas analysis: PaO₂ and oxygenation index (PaO₂/FiO₂). (M-R) Quantitative comparison of representative glycolysis-related metabolites, including fructose-6-phosphate, glucose-6-phosphate, glyceraldehyde-3-phosphate, dihydroxyacetone phosphate, and 3-phosphoglycerate. (S) Schematic diagram of the glycolytic pathway. Data are presented as mean ± SD. One-way ANOVA was used for panels A-C and F-L, and unpaired Student’s t-test was used for panels M-R

Recent studies have shown that lactate can act as an immunometabolic signal, regulating pulmonary macrophage phenotypes and participating in lung-protective processes. Immunofluorescence further showed increased CD206 (M2 macrophage marker) in HL, whereas CD86 (M1-associated markers) were most prominent in CL; HLA-DR expression levels were significantly higher in the HL group than in the CL group（p<0.0001)(Fig. 1E-H). This polarization pattern suggests that HAHP was associated with stronger anti-inflammatory effects in the lung [4]. In addition, superoxide dismutase (SOD) and tumor necrosis factor-α (TNF-α) reflect the extent of oxidative stress injury and the intensity of the inflammatory response.Serum ELISA demonstrated reduced SOD (p < 0.0001) and TNF-α(p < 0.01) in HL (Fig. 1I-J), indicating attenuation of oxidative/inflammatory responses. Functionally, oxygenation was better preserved in HL: the fall in PaO₂ was smaller, and PaO₂ remained significantly higher than in CL (p < 0.01) (Fig. 1 K-L), suggesting improved ventilatory efficiency and gas exchange. Notably, although blood glucose was slightly lower in HL than CL, lactate elevation was more pronounced and coincided with milder lung pathology, a more favorable inflammatory profile, and better oxygenation. Together, these results support the hypothesis that lactate elevation may function as an endogenous protective response that helps mitigate ALI [5].

Metabolomic analysis provided further mechanistic support. Compared with CL, the HL group showed higher levels of multiple glycolytic intermediates, including glucose-6-phosphate, glyceraldehyde-3-phosphate, dihydroxyacetone phosphate, and 3-phosphoglycerate (P > 0.05), among which fructose-6-phosphate and lactate levels were significantly increased (p < 0.05), suggesting that the HL group may exhibit a metabolism biased toward glycolysis.However, the elevation of glycolysis-related metabolites may also be associated with restricted entry of pyruvate into the tricarboxylic acid(TCA) cycle and alterations in oxidative phosphorylation capacity (Fig. 1M–S). These findings suggest a metabolic reprogramming pattern in high-altitude–conditioned rats characterized by enhanced glycolysis and lactate accumulation during LPS-induced ALI. In this context, Hypoxia-inducible factor-1α(HIF-1α)–driven glycolytic upregulation may produce a moderate rise in lactate that does not necessarily indicate worsening tissue hypoxia or metabolic failure; rather, it may represent a protective metabolic adaptation [6].

In summary, we agree with Tchatat et al. that lactate has therapeutic and organ-protective potential in critical illness. We extend this concept by providing evidence from a lung-protection perspective: in ALI, a moderate lactate increase was associated with reduced pulmonary inflammation, improved edema, preservation of tissue structure, and better gas exchange. High-altitude hypoxic preconditioning appears to induce a beneficial metabolic phenotype marked by enhanced glycolysis and lactate accumulation, which increases tolerance to acute inflammatory injury. These findings support reframing lactate from a terminal metabolic end-product to a signaling metabolite involved in immune regulation and organ protection.

Several limitations warrant mention. First, our assessments were limited to a single time point (6 h after model induction) and did not address longer-term repair or survival outcomes. Second, this study focused on a combined high-altitude hypobaric–hypoxic environment, without separately analyzing the individual effects of hypobaria or hypoxia.Future work should clarify the upstream mechanisms by which high-altitude adaptation enhances glycolysis and lactate signaling, and define the potentially dual roles of lactate in multi-organ injury and repair during sepsis.

Author contributions

Wantian Zhang: Methodology, Investigation, Visualization, Formal analysis, Writing - original draft. Ruixuan Wang: Methodology, Investigation, Formal analysis, Writing - original draft. Yu Zhang: Methodology, Investigation, Resources. Qian Lei: Conceptualization, Writing - review & editing, Project administration, Supervision. Si Zeng: Conceptualization, Writing - review & editing, Supervision, Project administration.

Funding

This work was supported by The National Natural Science Foundation of China (No. 82202071, 82470290) and Scientific research cooperation Project of North Sichuan Medical College (No. CBY25-ZXZDA06).

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

All animal protocols were reviewed and approved by the Ethics Committee for Basic and Clinical Research of Sichuan Provincial People’s Hospital (NO. 2024 − 419, Approved date: July 15, 2024).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.