Possible role of erythropoietin in the pathogenesis of chronic cor pulmonale

Email: Buemim{at}Unime.it

Sir,

As has been well demonstrated, the role played by erythropoietin, the growth factor of erythroid precursors, in general homeostasis is far wider than the simple regulation of the erythrocytic mass. This growth factor may also play a role in the development of several diseases, including chronic cor pulmonale (CCP).

CCP is a pathological condition characterized by right ventricular dilation and pulmonary hypertension. The pathophysiology of pulmonary hypertension is extremely complex. While hypoxic vasoconstriction appears to govern the entire process, the real cause of this condition is unknown; it is probably linked to the release of mediators acting on the vascular tone and leading to neurohormonal vascular hyperactivity that would, in the long term, cause chronic vasoconstriction [1]. Moreover, pulmonary hypertension and chronic hypoxia trigger muscular hypertrophy of the small artery walls with a further increase in vascular resistance [2].

Few studies have investigated the role of erythropoietin, the main growth factor of erythroid precursors, in the onset and progression of CCP. To assess the potential effect of erythropoietin on pulmonary artery pressure, we studied the effect of i.v. erythropoietin administration by means of a Swan–Ganz catheter and peripheral arterial catheter in 10 male subjects with CCP (mean age 68±3 years, history of chronic bronchitis and evidence of right ventricular dilation, pulmonary artery pressure >35 mmHg), and 10 healthy male non-smokers (69±2 years). Written informed consent was obtained from all subjects.

Subjects received an intravenous bolus of rHuEpo (erythropoietin ß 70 U/kg). At 0, 10 and 30 min we evaluated the mean arterial blood pressure, mean pulmonary arterial blood pressure, pulmonary vascular resistance index and the systemic vascular resistance index. The results are shown in Table 1. Statistical analysis was done using the ANOVA one-way test. The value P<0.05 was considered significant. Data were expressed as mean values±SD.


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Table 1. Mean arterial blood pressure, mean pulmonary arterial blood pressure, pulmonary vascular resistance index, systemic vascular resistance index, serum EPO and HT in CCP subjects and in healthy controls after administration of 70 UI/kg rHuEPO

 
Our data appear to confirm that erythropoietin has an effect on vascular pulmonary resistance, causing a significant increase in pulmonary vascular resistance index (PVRI) both in healthy people and in CCP patients. We made a haemodynamic evaluation in two patients with hypovolaemic shock using a catheter placed in the pulmonary artery. Erythropoietin administration determined an increase in pulmonary vascular resistance and in mean pulmonary artery pressure [3].

In transgenic mice that constitutively over-express the human erythropoietin gene in an oxygen independent manner, it has been demonstrated that pulmonary artery pressure is increased in vivo. Likewise, in heterozygous Hypoxia-Inducible Factor-1{alpha}-deficient (HIF1{alpha} +/–) mice, the key factor in erythropoietin regulation, following hypoxia a significantly delayed development of polycythaemia, pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodelling are seen [4]. The action of erythropoietin on vascular pulmonary resistance could be determined by the capacity of erythropoietin to influence vascular tone.

In our previous experience on studying the blood flow of the pre-tibial muscle, we found an erythropoietin induced reduction in post-ischaemic vasodilatation [5]. Moreover, in anaesthetised rats with haemorrhagic shock induced by intermittent bleeding, erythropoietin administration significantly increased the mean arterial pressure [6]. Erythropoietin also seems to be able to inhibit acetylcholine induced cutaneous vasodilation and can stimulate the endothelial release of endothelin, and inhibit nitric oxide, a potent vasodilator [7].

The action of erythropoietin on the physiopathology of CCP may, however, not be limited to its vasomotor effect on the pulmonary circulation; it may also impact on pulmonary vascular remodelling. It is well known that erythropoietin can influence the proliferation process of cell types other than erythroid precursors, such as endothelial progenitor cells and smooth muscle cells [8]. In erythropoietin-transgenic mice, the relative lung weight is increased, the interalveolar septa have a greater thickness and this is accompanied by interstitial and perivascular fibrosis [9]. Foster et al. [10] demonstrated that developmental lung growth involves paracrine erythropoietin signalling with parallel upregulation of EPOR (erythropoietin receptor). The chronic increase in endogenous erythropoietin concentrations present in patients with chronic obstructive broncopathy may therefore contribute to the thickening of the arterial wall of the pulmonary vessels, typical of chronic pulmonary heart disease.

In conclusion, although erythropoietin is only one of the many factors activated during the reduction in pO2, the role of the hormone in the development of pulmonary hypertension and pulmonary vascular remodelling in patients with cor pulmonale may be of clinical relevance.

Conflict of interest statement. None declared.

Alessandro Allegra1, Maria Stella Giacobbe2, Ermanno Corvaia1, Maurizio Cinquegrani1, Elio Corvaja3, Giovanna Giorgianni4 and Michele Buemi2

1 Department of Internal Medicine2 Chair of Nephrology3 Department of Pneumology4 Department of Clinical Pathology University of Messina (Italy)

References

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  3. Allegra A, Galasso A, Siracusano L et al. Administration of recombinant erythropoietin determines increase of peripheral resistances in patients with hypovolemic shock. Nephron 1996; 74: 431–432[ISI][Medline]
  4. Creutiziz A, Caspary L, Nonnast-Daniel B. Skin microcirculation and regional peripheral resistance in patients with chronic renal anaemia treated with recombinant human erythropoietin. Eur J Clin Invest 1990; 2: 219–223
  5. Buemi M, Allegra A, Lagana A et al. Is erythropoietin-induced hypertension a phenomenon due to the intracellular Ca++ mobilisation? Int Angiol 1994; 13: 75–77[ISI][Medline]
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  7. Calapai G, Marciano MC, Corica F et al. Erythropoietin protects against brain ischemic injury by inibition of nitric oxide formation. Eur J Pharmacol 2000; 401: 349–356[CrossRef][ISI][Medline]
  8. Bahlmann FH, De Groot K, Spandau JM et al. Erythropoietin regulates endothelial progenitor cells. Blood 2003; 2: 18
  9. Briest W, Homagk L, Baba HA et al. Cardiac remodelling in erythropoietin-transgenic mice. Cell Physiol Biochem 2004; 14: 277–284[CrossRef][ISI][Medline]
  10. Foster DJ, Moe OW, Hsia CC. Upregulation of erythropoietin receptor during postnatal and postpneumonectomy lung growth. Am J Physiol Lung Cell Mol Physiol 2004; 287: 1107–1115[CrossRef]




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