Erythrocytes

Physiology and Pathophysiology

Florian Lang, Michael Föller

• Publisher: ICP
• Year: 2012
• ISBN:
  9781908977083
• Topic: Medicine
• Subtopic: Hematology

The book covers the functional significance and properties of erythrocytes, their generation, senescence, and suicidal death. It further summarizes knowledge about hormones influencing erythrocyte formation including erythropoietin as well as disorders affecting and involving erythrocytes such as anemia, malaria, and sepsis.

This seminal work forms a unique reference on the most abundant cell type in mammals and will be an invaluable resource for students in the life sciences.

Contents:

• Functional Significance of Erythrocytes (Wolfgang Jelkmann)
• Properties and Membrane Transport Mechanisms of Erythrocytes (Peter K Lauf and Norma C Adragna)
• Erythropoiesis (Maxim Pimkin and Mitchell J Weiss)
• Erythrocyte Senescence (Giel JCGM Bosman, Frans LA Willekens and Jan M Werre)
• Eryptosis, the Suicidal Death of Erythrocytes (Florian Lang, Stephan Huber and Michael Föller)
• Regulation of Red Cell Mass by Erythropoietin (Johannes Vogel and Max Gassmann)
• Anaemia (Gordon W Stewart and Michael Watts)
• Erythrocytes and Malaria (Henry M Staines, Elvira T Derbyshire, Farrah A Fatih, Amy K Bei and Manoj T Duraisingh)

Readership: Students and undergraduates in biology, researchers and professionals involved in clinical hematology, malaria or any erythrocyte related research.

1

Functional Significance
of Erythrocytes

Wolfgang Jelkmann^∗

Institute of Physiology, University of Lübeck, Ratzeburger Allee 160,
D-23562 Lübeck, Germany

1.1 Introduction

Erythrocytes (from ancient Greek erythrós for “red” and kýtos for “cavity”) are the most frequent cellular elements (95%) in blood. They develop in hematopoietic tissues (the bone marrow in adult humans) and circulate for 100–120 days until they are engulfed by macrophages. Human erythrocytes are anucleated discs full of hemoglobin (Hb), the oxygen (O₂) binding hemeprotein that causes the blood’s red color. Erythrocytes transport O₂ from the lung to the peripheral tissues. In addition, erythrocytes expedite the carbon dioxide (CO₂) transport in blood, have buffer function, and can release vasoactive substances.

1.2 Historical Perspective

The Biblical phrase “for the life of the flesh is in the blood” (Moses 4th book; Leviticus 17:11) unveils that blood was considered the spirit of life in the early days. In ancient medicine, somatic and psychic diseases were often related to an unfit blood composition. Accordingly, physicians advocated bloodletting as a primary therapy. The blood of a healthy creature was believed to make a human recipient powerful and courageous if ingested or used for a bath.^1,2 Interestingly, the archaic supposition that blood is a medium transferring individual properties has received recent verification with the intriguing finding that the chemosensory identity through odor is altered in rodents after hematopoietic stem cell transplantation.³ Peptides deriving from molecules encoded by the major histocompatibility complex (MHC) gene family are thought to function as olfactory signals.⁴

1.2.1 Characterization of erythrocytes

Red blood cells were first seen under a microscope in the 1660s, by the Dutch biologist Jan Swammerdam, who studied frog blood, and the Italian anatomist Marcello Malpighi, who studied hedgehog blood. Shortly thereafter, Antonie van Leeuwenhoek from Delft in the Netherlands provided a detailed microscopic characterization of erythrocytes. He correctly measured the diameter of human erythrocytes to be 7.5 μm. In 1675, van Leeuwenhoek noted: “I am apt to imagine, that those sanguineous globuls in a healthy Body must be very flexible and pliant, if they shall pass through the small capillary Veins and Arteries, and that in their passage they change into an oval figure, reassuming their roundness when they come into a larger room”.⁵ In 1843, the pathologist Gabriel Andral of Paris, sometimes referred to as the founder of scientific hematology, introduced the term “anemia” as the opposite of plethora. In 1852, the physiologist Karl von Vierordt of Tübingen presented a micrometer method for counting erythrocytes in diluted blood samples.⁶ Von Vierordt estimated the number quite rightly at 5 Mio per μL blood for men. Subsequently, Georges Hayem of Paris developed “Hayem’s solution” for blood cell counting. This pioneering work has been reviewed previously.⁷ In 1868, Ernst Neumann of Königsberg and Giulio Bizzozero of Berlin reported the myeloid origin of mammalian erythrocytes.⁸ George Gulliver⁹ first provided a comprehensive description of the size and shape of the red corpuscles (“with drawings of them to a uniform scale, and extended and revised tables of measurements”) of various vertebrate species. In the 1890s, Israel and Pappenheim succeeded in differentiating the stages of erythrocytic precursors, i.e. the transition from basophilic to polychromatic, hemoglobinized, erythroblasts.^10,11

1.2.2 Hb and gas transport

In 1746, the chemist Vincenzo Menghini of Bologna reported that iron (“ferrum”) is concentrated in the erythrocytes and that this causes the red color of the blood.¹² Heinrich Gustav Magnus of Berlin first demonstrated that there is more O₂ and less CO₂ in arterialized compared to venous blood.¹³ The important role of erythrocytes as O₂ carriers was recognized in the second half of the 19th century (Table 1.1).

In 1862, the physiological chemist Felix Hoppe-Seyler of Tübingen isolated and crystallized the O₂ binding blood-borne protein. He presented the absorption spectra of the protein and gave it the name “hemoglobin”.¹⁴ Hoppe-Seyler also demonstrated that Hb can reversibly bind O₂, resulting in “oxyhemoglobin”. The physiologist Eduard von Pflüger of Bonn recognized that the gas exchange between the blood and the tissue occurs by the process of diffusion.¹⁵ In 1878, the English neurologist William Richard Gowers developed a device (“haemocytometer”) for the measurement of the Hb concentration [Hb] in blood. In 1904, Christian Bohr, Karl Albert Hasselbalch, and August Krogh from Copenhagen described the sigmoid Hb-O₂ dissociation curve and the influence of CO₂ on the binding of O₂ to Hb (“Bohr effect”).¹⁶ Hb-O₂ binding proved to be affected by pH, ionic strength, and temperature. Carl Gustav von Hüfner of Tübingen and associates calculated that the molecular weight of Hb is 16,700¹⁷ — which holds true for the Hb subunit — and showed that 1 g of crystalline Hb can bind up to 1.34 mL O₂.¹⁸ In 1910, the physiologist Archibald Vivian Hill of Cambridge, England, formulated an Hb aggregation hypothesis and proposed a simple equation for the Hb-O₂ dissociation curve: SO₂/(1 – SO₂) ≈ PO₂ⁿ, where SO₂ is the O₂ saturation ratio and PO₂ the O₂ partial pressure in mmHg, with slope n (“Hill coefficient”) amounting to about 2.7.¹⁹ Hill received the Nobel Prize in Physiology or Medicine 1922 (shared with Otto Fritz Meyerhof) “for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”.

Table 1.1 Seminal studies of the respiratory function of erythrocytes.

Year	Study	Investigators
1837	Blood gas measurements	H Gustav Magnus
1862	Discovery of reversible O2 binding to Hb	Felix Hoppe-Seyler
1868	Role of bone marrow in hematopoiesis	Ernst Neumann, Guilio Bizzozero
1872	Tissue respiration	Alexander Schmidt, Eduard FW Pflüger
1880	Respiratory function at high altitude	Paul Bert, Denis Jourdanet
1904	Sigmoid Hb/O2 binding curve and pH effect	Christian Bohr, Karl Hasselbalch and August Krogh
1909	Puffering of H^+ by Hb	Lawrence Henderson
1910	Hb aggregation hypothesis	Archibald Hill
1936	Geometry of O2 binding	Linus Pauling and Charles Coryell
1938	O2 dependent conformational change of Hb	Felix Haurowitz
1970	“T-” and “R-” structures of Hb	Max Perutz

In 1925, Gilbert Smithson Adair of Cambridge, England, first recognized the tetrameric structure of the Hb molecule and that it contains four hemes.²⁰ In the same year, the American surgeon George Whipple discovered that iron, stored in the liver, was essential for heme synthesis and erythropoiesis. The development of a treatment for pernicious anemia — a fatal disease caused by atrophic gastritis, lack of intrinsic factor, and subsequent loss of the ability to absorb vitamin B₁₂ — earned George Whipple, George Minot, and William Murphy the Nobel Prize in Physiology or Medicine 1934 “for their discoveries concerning liver therapy in cases of anaemia”. The German chemist Hans Fischer characterized the heme structure and eventually synthesized it in 1929. The manner in which the O₂ is bound to the heme iron was first recognized by Linus Pauling and Charles Coryell of Pasadena in 1936, when they showed an ozone-type binding.²¹ Pauling received the Nobel Prize in Chemistry 1954 “for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances”. In 1938, Felix Haurowitz of Prague observed that Hb forms different crystals in the absence and presence of O₂, indicating that the protein can undergo a conformational change.²² This finding stimulated the Austrian chemist Max Ferdinand Perutz in his ambitious project of using X-ray crystallography to uncover the structure-function relationship of Hb, which he performed in Cambridge, England. It took Perutz almost 30 years of work, until he had unravelled the tertiary structure of the protein and demonstrated cooperativity between its four subunits. Perutz was awarded the Nobel Prize for Chemistry 1962, shared with John Cowdery Kendrew, “for their studies o...

Table of contents

• Cover Page
• Halftitle
• Title
• Copyright
• Contents
• Abbreviations
• 1 Functional Significance of Erythrocytes
• 2 Properties and Membrane Transport Mechanisms of Erythrocytes
• 3 Erythropoiesis
• 4 Erythrocyte Senescence
• 5 Eryptosis, the Suicidal Death of Erythrocytes
• 6 Regulation of Red Cell Mass by Erythropoietin
• 7 Anaemia
• 8 Erythrocytes and Malaria
• Index