Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension.

Summary

In murine hypoxic PH, resident interstitial macrophages proliferate and produce CCL2, while recruited CCR2+ macrophages express thrombospondin-1 to activate TGF-β, driving vascular disease. Blocking monocyte recruitment (CCL2 neutralization or CCR2 deficiency) suppresses hypoxic PH, and human ascent data show TSP-1/TGF-β increases prevented by dexamethasone; dexamethasone similarly blunts CCL2/CCR2+ recruitment in mice.

Key Findings

• Hypoxia-exposed mice showed proliferation of resident interstitial macrophages expressing CCL2 and recruitment of CCR2+ macrophages expressing thrombospondin-1 that activates TGF-β.
• Blocking monocyte recruitment via CCL2-neutralizing antibody or bone marrow CCR2 deficiency suppressed hypoxic pulmonary hypertension.
• In humans ascending from 225 m to 3500 m, plasma thrombospondin-1 and TGF-β increased; dexamethasone prophylaxis blocked these increases and, in mice, suppressed CCL2 and CCR2+ monocyte recruitment.

Clinical Implications

Supports therapeutic exploration of CCR2/CCL2 blockade and modulation of TSP-1/TGF-β signaling, and suggests steroid prophylaxis might mitigate hypoxia-related PH risk in select contexts (e.g., high-altitude exposure), pending clinical trials.

Limitations

• Generalizability from hypoxia models to diverse PH etiologies remains uncertain.
• Steroid prophylaxis has potential systemic side effects; optimal target, timing, and duration require clinical validation.

Future Directions

Clinical trials to test CCR2/CCL2 axis inhibitors or TSP-1/TGF-β modulation in hypoxia-related PH; define biomarkers for patient selection and response; explore steroid-sparing strategies.