Chronic hypoxia (CH) is characterized by long‐term hypoxia that is associated with microvessel proliferation and basal membrane (BM) degradation in tissues. The IL‐6/JAK2/STAT3/MMP‐9 pathway has been described in a variety of human cancers and plays an essential role in microvessel proliferation and BM degradation. Therefore, this study investigated the role of the IL‐6/JAK2/STAT3/MMP‐9 pathway in hypoxia‐mediated microvessel proliferation and BM degradation in the rat bone marrow. Eighty pathogen‐free Sprague Dawley male rats were randomly divided into four groups (20 per group)—control group, CH group (exposed to hypoxia in a hypobaric chamber at a simulated altitude of 5000 m for 28 d), CH + STAT3 inhibitor group (7.5 mg/kg/d), and CH + DMSO group. Microvessel density (MVD) and BM degradation in the bone marrow were determined by immunofluorescence staining and transmission electron microscopy. Serum IL‐6 levels were assessed by enzyme‐linked immunosorbent assay (ELISA), and the levels of P‐JAK2, P‐STAT3, and MMP‐9 were assessed by western blot analysis and real‐time reverse transcription PCR (RT‐PCR). Hypoxia increased serum IL‐6 levels, which in turn increased JAK2 and STAT3 phosphorylation, which subsequently upregulated MMP‐9. Overexpression of MMP‐9 significantly promoted the elevation of MVD and BM degradation. Inhibition of STAT3 using an inhibitor, SH‐4‐54, significantly downregulated MMP‐9 expression and decreased MVD and BM degradation. Surprisingly, STAT3 inhibition also decreased serum IL‐6 levels and JAK2 phosphorylation. Our results suggest that the IL‐6/JAK2/STAT3/MMP‐9 pathway might be related to CH‐induced microvessel proliferation and BM degradation in the bone marrow.

Rationale: High-altitude polycythemia (HAPC) is a common disease in high-altitude areas characterized by excessive erythrocyte proliferation and severe hypoxemia. Recently, the incidence of ureteral calculi has risen. However, cases of ureteral calculi associated with HAPC have not been reported. Patient concerns: We present the cases of 2 patients (26-year-old female, Case 1; 31-year-old male, Case 2) with HAPC who were born in the lowlands and worked in areas of high altitudes. Both patients were admitted to the hospital with acute severe pain in the ureter as the first symptom. Diagnoses: Urological examinations confirmed the presence of a ureteral stone. Interestingly, the biochemical tests showed elevated serum uric acid levels, and the calculous component analysis suggested anhydrous uric acid. Interventions: In the first case, the patient underwent extracorporeal shock wave lithotripsy. In the second case, the patient underwent right ureteroscopy and right ureteral stenting. The patient received postoperative anti-inflammatory, hemostatic, and rehydration therapy. Outcomes: Both patients recovered well with no recurrences observed upon regular re-examinations. Lessons: Recently, extensive research has demonstrated a significant correlation between hyperuricemia and HAPC. Therefore, we speculated that the occurrence of ureteral calculi among immigrants to the plateau might be related to hyperuricemia associated with HAPC. This case report and literature review highlights that the prevention of ureteral calculi in patients with polycythemia who immigrate to the plateaus from high-altitude areas should be considered. Additionally, the serum uric acid levels and urine pH should be monitored regularly.