Background: Surfactant Protein D (SP-D) is a critical immunomodulatory collectin maintaining alveolar homeostasis. Obstructive sleep apnea (OSA)-related intermittent hypoxia (IH) disrupts pulmonary surfactant integrity; however, severity-dependent SP-D dynamics remain incompletely characterized. This study explores SP-D as a potential indicator of IH-induced alveolar stress and evaluates whether Galectin-3 (Gal-3) inhibition modulates surfactant homeostasis. Methods: Forty adult male Sprague-Dawley rats (8 per group) were randomized to Control (normoxia), Moderate IH (MIH; 15–30 events/hour), Severe IH (SIH; 30–60 events/hour), MIH + Gal-3 inhibitor (Modified Citrus Pectin, 800 mg/kg/day), or SIH + Gal-3 inhibitor. IH exposure lasted 8 h/day for 10 days. Outcomes included circulating SP-D, Surfactant Protein B (SP-B), inflammatory markers, physiological parameters, and histopathological lung injury scores assessed via American Thoracic Society guidelines. Results: SP-D levels showed numerical reductions with increasing IH severity (Control: 1969.07 pg/mL [IQR: 262.15]; SIH: 1404.30 pg/mL [IQR: 351.88]), representing a 28.6% decrease. However, between-group variability resulted in non-significant omnibus testing (Kruskal–Wallis p = 0.187). Gal-3 inhibition elevated SP-D levels, particularly in severe IH (2133.95 pg/mL [IQR: 1240.70]), though high inter-individual variability was observed (CV = 58.1%). SP-B showed significant suppression under moderate IH (p = 0.019) with restoration by treatment. Exploratory correlation analysis revealed moderate positive associations between SP-D and heart rate (r = 0.587) and respiratory rate (r = 0.419) in severe IH, though these did not reach statistical significance (p = 0.126 and p = 0.301, respectively). Histologically, severe IH induced diffuse alveolar damage (total lung score: 19.67 ± 0.82). Gal-3 inhibition produced context-dependent effects: protective in severe IH but paradoxically exacerbating inflammation under moderate IH (29.20 ± 4.64 vs. 20.00 ± 4.34; p < 0.05). Gal-3 inhibition significantly attenuated cardiac injury (injury score: 0.00 ± 0.00 vs. 7.17 ± 0.75 in severe IH; p < 0.001, η² = 0.859). Conclusions: SP-D demonstrates severity-associated alterations consistent with alveolar epithelial stress during IH, though high variability limits definitive biomarker validation in this sample. Gal-3 inhibition modulates surfactant homeostasis and attenuates cardiopulmonary injury in a context-dependent manner. These findings support further investigation into SP-D as a component of multimodal severity stratification in OSA and highlight Gal-3 inhibition as a context-dependent anti-inflammatory strategy, pending validation in larger cohorts with tissue-level confirmation.

Background: Intermittent hypoxia (IH), the pathophysiological hallmark of obstructive sleep apnea (OSA), promotes oxidative stress and cardiovascular remodeling. Galectin-3 (Gal-3) is a key mediator of hypoxia-associated inflammatory cardiac injury. ALKBH5, an m6A RNA demethylase detectable in plasma, has not been systematically characterized during hypoxic cardiovascular stress. This experimental study examined plasma ALKBH5 responses to graded IH and evaluated whether pharmacologic Gal-3 inhibition with modified citrus pectin (MCP) modulates circulating ALKBH5 levels and associated cardiac histopathology. Methods: Male Sprague–Dawley rats ( n = 40) were randomized to five groups ( n = 8/group): normoxia control; moderate IH (MIH; nadir FiO ₂ 10%–12%); severe IH (SIH; nadir FiO ₂ 5%–7%); MIH with MCP (800 mg/kg/day); and SIH with MCP. IH exposure was applied for 8 h/day over 10 days. Endpoint plasma ALKBH5 and Gal-3 concentrations were quantified by ELISA. Cardiac histology was assessed using blinded semi-quantitative injury scoring. Group comparisons were performed using Kruskal–Wallis tests with Dunn's post-hoc correction, and factorial effects were analyzed using aligned rank transform (ART) ANOVA. Correlations were explored using Spearman's rank correlation coefficients due to small sample size and non-normal distributions. Results: Plasma Gal-3 increased in a severity-dependent manner with IH (Control: 18.4 ± 3.2; MIH: 34.7 ± 5.8; SIH: 48.2 ± 7.1 ng/mL; p < 0.001) and was significantly reduced by MCP treatment (36%–45% reduction; p < 0.01), confirming effective target engagement. Plasma ALKBH5 [median (IQR)] was significantly reduced in SIH compared with controls [691 [562] vs. 2,048 [1,094] pg/mL; p = 0.008], while MIH showed a non-significant trend toward reduction [1,213 (951) pg/mL; p = 0.089]. MCP treatment was associated with higher plasma ALKBH5 concentrations in both IH groups [MIH + MCP: 1,866 [1,698]; SIH + MCP: 1,807 [1,595] pg/mL; p < 0.05 vs. respective IH groups]. ART ANOVA demonstrated a significant main effect of Gal-3 inhibition on circulating ALKBH5 independent of hypoxic severity [F(1,28) = 21.28, p < 0.001, partial η ² = 0.381]. Histological analysis revealed marked myocardial injury in untreated IH groups, whereas MCP-treated animals exhibited markedly attenuated histopathological injury within the limits of semi-quantitative histological assessment. Conclusion: Severe intermittent hypoxia has been linked to a drop in circulating ALKBH5 levels, whereas pharmacological inhibition of galectin-3 has been associated with maintaining plasma ALKBH5 concentrations and a significant reduction of hypoxia-induced myocardial pathological damage in an experimental rat model. These findings suggest circulating ALKBH5 as a hypoxia-responsive molecular signal controlled by inflammatory pathways; however, more mechanistic and longitudinal investigations are necessary to characterize its biological significance and possible translational value.