Chest

Chest

Volume 106, Issue 1, July 1994, Pages 236-243
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Review
Chronic Hypoxic Pulmonary Hypertension: Cell Biology to Pathophysiology

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Comparisons: Clinical and Experimental

Accurately defining the complexity of the pulmonary vascular response to prolonged durations of reduced oxygen tension has been complicated by the myriad of factors demonstrated to have significance in disease development, both clinically and experimentally. Interspecies and intraspecies variation has been observed in virtually every aspect of study ranging from experimental protocol to results. Bovine and porcine species are quite susceptible to the pulmonary hemodynamic complications of

Vasoconstriction: General Characteristics

In experimental animals maintained under prolonged hypoxic conditions or in human disease states associated with chronic alveolar hypoxia, an abnormally heightened tone appears to persist in the resistance-sized vessels of the pulmonary circulation. This sustained vasospasm is mediated through the contraction of smooth muscle cells located in the precapillary arterioles and represents a potentially reversible physiologic process regardless of disease duration or severity. The demonstrated

Vasoconstriction: Acute and Chronic Comparison

Acute hypoxic vasoconstriction is an inherent property of the lung designed to divert blood flow from poorly ventilated alveoli and improve local ventilation/perfusion relationships. When generalized, this same process can result in significant increases in PVR and consequent right ventricular strain. Short-term exposure of the pulmonary circulation to reduced levels of oxygen tension both in vivo and in vitro elicits an immediate vasoconstrictive response that is totally reversible upon return

Sustained Vasospasm: Mechanisms

Basal pulmonary circulatory tone is maintained by a dynamic balance of vasoconstrictor and vasodilatory influences acting on the PVSMC located in the precapillary resistance vessels of the lung. This interaction is controlled by factors both intrinsic and extrinsic to the smooth muscle itself. Under conditions of chronic generalized alveolar hypoxia, there is a shift favoring PVSMC contraction and a heightened overall vascular tone. Mechanistically, this imbalance could result from either an

Structural Remodeling: General Characteristics

Under conditions of chronic generalized alveolar hypoxia, the complexity of pathologic structural remodeling has been demonstrated throughout the entirety of the pulmonary circulation and all the structural layers of the arterial wall. The changes common to all chronically hypoxic disorders regardless of disease etiology or experimental condition include (1) the abnormal deposition of increased amounts of collagen and elastin within the adventitia, (2) medial smooth muscle cell hypertrophy and

Structural Remodeling: Matrix Components

The importance of extracellular matrix deposition in contributing directly to the elevation in PVR was first demonstrated in animal studies utilizing the nonspecific lathyrogen (B-aminopropionitrile) to inhibit both collagen and elastin formation.34 This pharmacologic intervention resulted in significant structural and hemodynamic improvement. Subsequent studies by these same investigators later demonstrated equal efficacy with the collagen-specific inhibitor cis-hydroxyproline not only in

Structural Remodeling: Smooth Muscle Cell Abnormality

The changes in smooth muscle cell histologic features are thought to represent abnormalities of growth; replication and hypertrophy in large-sized vessels and maturation and development in smaller ones. in vitro studies have clearly demonstrated that hypoxia alone is incapable of directly stimulating PVSMC DNA synthesis and replication.41 Consequently, the potential role of currently known cellular mitogens and other growth regulatory substances as being etiologically implicated in mediating

Therapy: Preventive

Conceptually, as a result of local inhomogeneity, the multitude of peripheral airways along with their accompanying vessels are exposed to variable levels of oxygen concentration dependent on the degree of reduction in inspired oxygen concentration, the degree of obstruction in chronic airway disorders, or the degree of ineffective ventilation associated with nonparenchymal respiratory diseases. In humans, a threshold or critical value of oxygen reduction at the alveolus has not yet been

Therapy: Established Pulmonary Hypertension

Even once manifest, initial treatment of pulmonary hypertension in clinically stable situations remains directed at the primary disease with hopes of secondary improvement in its hemodynamic sequelae. Once this aspect of therapy is optimized or the disease reaches a stage deemed irreversible, then specific efforts may be directed toward the pulmonary vascular processes per se. Current options are limited to vasodilators or addition of supplemental oxygen. However, it must be realized that

Conclusion

In conclusion, pulmonary hypertension is a frequent hemodynamic complication of a wide spectrum of disease processes whose only common abnormality is chronic alveolar hypoxia. The development of the increase in PAP is mediated by two interdependent vascular mechanisms: (1) persistent vasospasm and (2) structural remodeling. The combination of these physiologic and pathologic processes imposes a mechanical and obliterative burden on the pulmonary circulation that cannot be dissipated by normal

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REFERENCES (50)

  • WeirEK et al.

    The genetic factor influencing pulmonary hypertension in cattle at high altitude

    Cardiovasc Res Reses

    (1974)
  • AgostoniP et al.

    Nifedipine reduced pulmonary pressure and vascular tone during short- but not long-term treatment of pulmonary hypertension in patients with chronic obstructive pulmonary disease

    Am Rev Respir Dis Disis

    (1984)
  • WilsonRH et al.

    The effects of breathing 99.6 percent oxygen on pulmonary vascular resistance and cardiac output in patients with pulmonary emphysema and chronic hypoxia

    Ann Intern Med Meded

    (1955)
  • AnthonisenNR

    Long-term oxygen therapy

    Ann Intern Med

    (1983)

  • Nocturnal Oxygen Therapy Trial Group Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease

    Ann Intern Med

    (1980)
  • VoelkelNF

    Mechanisms of hypoxic pulmonary vasoconstriction

    Am Rev Respir Dis

    (1986)
  • MurrayTR et al.

    Hypoxic contraction of cultured pulmonary vascular smooth muscle cells

    Am J Respir Cell Mol Biol Bioliol

    (1990)
  • McMurtryIF et al.

    Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs

    Circ Res Reses

    (1976)
  • PostJM et al.

    Direct role of potassium channel inhibition in hypoxic pulmonary vasoconstriction

    Am J Physiol Physiolhysiol

    (1992)
  • DemiryurekAT et al.

    The role of endothelium in hypoxic constriction of human pulmonary artery rings

    Am Rev Respir Dis Disis

    (1993)
  • Burke-WolinTM et al.

    Inhibition of cGMP-associated pulmonary arterial relaxation to H2O2 and O2 by ethanol

    Am J Physiol Physiolhysiol

    (1990)
  • SimonneauG et al.

    Inhibition of hypoxic pulmonary vasoconstriction by nifedipine

    N Engl J Med

    (1981)
  • AbrahamAS et al.

    Factors contributing to the reversible pulmonary hypertension of patients with acute respiratory failure studied by serial observations during recovery

    Circ Res

    (1969)
  • ThompsonBT et al.

    Acute and chronic hypoxic pulmonary hypertension in guinea pigs

    J Appl Physiol

    (1989)
  • RodmanDM

    Chronic hypoxia selectively augments rat pulmonary artery Ca++ and K+ channel mediated relaxation

    Am J Physiol

    (1992)

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    Copyright © 1994 The American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.