Who among the following is most closely associated with the homeostatic medical approach to stress?

Introduction

The liver has been called the “the custodian of the milieu intérieur.” Consistent with its many varied metabolic functions, the liver has a complex transcriptome and proteome. The normal liver has many diverse functions, including synthesis of vitamins and proteins, bile production, and immune defense, as well as metabolism of carbohydrates, lipids, and toxins. Despite being only 2.5% of body weight, the liver receives 25% of cardiac output, which is essential for maintaining its metabolic and synthetic functions. The functional unit of the liver is the hepatic lobule, which is arranged in an organized, repeating fashion around a central venule to form the intact organ (Figure 78.1). Liver injury is characterized by progressive fibrosis tissue deposition within the lobule, leading to the eventual disruption of normal lobular architecture that is characteristic of cirrhosis (Figure 78.2) (Friedman, 2000). In the genomic era, the molecular classification of fibrosis has been limited, with cirrhosis development predominantly characterized by morphological changes.

Cirrhosis is the pathogenic hallmark of advanced liver injury. Cirrhosis is morphologically defined by distortion of hepatic architecture by dense bands of fibrosis “scar,” leading to “islands” or nodules of hepatocytes (Friedman, 2000). The causes of cirrhosis are varied, with many unique aspects based on etiology (Table 78.1). The teleological role of this response is the confinement of injury while maintaining hepatic function. Cirrhosis is a premalignant condition, with virtually all cases of liver cancer [also known as hepatocellular carcinoma (HCC)] developing in individuals with cirrhosis. Various intrahepatic cell populations are essential in understanding the development of cirrhosis. The pivotal cell involved in the fibrosis leading to cirrhosis is the hepatic stellate cell. However, the functional unit of the liver is the hepatocyte, the cell type from which HCC develops. The mechanisms of fibrosis leading to cirrhosis will be discussed in the context of understanding the pathogenic mechanisms by which this process evolves. Genomic medicine promises new insights into the pathogenesis of fibrosis, and brings the promise of individualized, predictive medicine aiming to avoid cirrhosis and the sequelae of liver failure and HCC.

Table 78.1. Causes of cirrhosis and/or chronic liver disease

Homeostasis

Cannon developed French physiologist Claude Bernard's (1813–78) concept of milieu intérieur (internal milieu) into his own concept of homeostasis to describe the product of the “coordinated physiological processes, which maintain most of the steady states in the organism.” Cannon considered homeostasis to be a form of organized self-government, one that requires a coordinated system of physiological mechanisms that act automatically to maintain constancy of the internal environment in response to changes in the external environment. Cannon argued that rapid activation of homeostatic systems, especially neuroendocrine responses of the ‘sympathico-adrenal system,’ produces anticipatory and compensatory adjustments that both preserve the internal environment and enhance the probability of survival. Cannon's influential ideas on homeostasis were outlined in The Wisdom of the Body (1932).

Fatigue as an Adaptive Response to Stress

One of the early theories of fatigue postulates a disequilibrium of the “milieu interieur” as a primary etiological factor, in which stress plays a potentially critical role. In later models, fatigue has been conceptualized as the result of an imbalance between “demand and supply” or as a breakdown in adaptation to stressful challenges.12 From this perspective, the aforementioned “diagnostic” approach falls short in identifying the “normal” fatigue response to environmental demands.

The association between stress and fatigue becomes clear when examining Selye’s General Adaptation Syndrome model. In this model, the individual response to stress has three phases: (1) acute/alarm (similar to the fight-or-flight response); (2) resistance (associated with sustained stressors and concomitant elevated activity of a wide range of biological systems, including hypothalamic-pituitary-adrenal [HPA]-axis activation); and (3) recovery/exhaustion (recovery when the stressor is successfully “removed,” and exhaustion when the stressor remains present and biological resources are gradually depleted). The third “exhaustion” stage is of particular relevance to the stress-fatigue relationships. From this perspective, fatigue can be conceptualized as an adaptive response to prolonged stress such that the individual will at some point discontinue (ineffective) efforts to alleviate a chronic stressor. In other words, the behavioral consequences of exhaustion may be adaptive in the sense that they could attenuate potentially adverse effects of long-term depletion of biological resources.

Stress Normal and Abnormal, and Homeostasis

In the middle of the nineteenth century Claude Bernard defined the concept of the milieu interieur, his point being that the organism regulates all of the physiological processes going on in the body (under the skin). Early in the twentieth century, Walter Cannon hypothesized that the organism seeks homeostasis, that is, there is an optimal status for the milieu interieur, and the organism attempts to maintain that set of conditions. While there is much truth to this concept, it has been found to be an oversimplification. For example, most physiological processes have been shown to fluctuate normally over predetermined time cycles, for example, the circadian (around 24 h) rhythm and the monthly menstrual cycle.

In the context of homeostasis, ignoring the definitional problem, stress can be understood as a perturbation of this set of psychological, physiological, biochemical, and even gene expression states. A fundamental question thus arises: is the stress response – the organism's response to the stressor – a normal reaction? And, if so, what is its function?

Cannon gave an answer to this question, although he was not thinking exactly in terms of the stress response. He viewed the various physiological changes that occur as preparing the organism for fight or flight, in other words, for action. Extensive study of the multitude of reactions that occur during the response to the stressor has generally been consistent with this hypothesis. In short, Cannon was largely correct.

Perhaps the scientist most closely associated with the concept of stress was Hans Selye. He called it the general adaptation syndrome (GAS). He viewed the stress response somewhat differently, not clearly as an adaptive mechanism but as evidence of dysfunction, at least in its more extreme form. In short (admittedly an oversimplification), both Cannon and Selye viewed the changes that are now called the stress response as normative, that is, always or almost always occurring when a stressor is present. However, Cannon viewed the response as adaptive and healthy, while Selye viewed it, at least in its more severe form, as destructive.

The Concept of Homeostasis

To place Cannon’s research on the fight-or-flight response in context, it is important to first consider his path-breaking work on homeostasis, which was an outgrowth of earlier studies in France. Beginning in the mid-nineteenth century and continuing until his death in 1878, the renowned French physiologist, Claude Bernard, advanced the theory that bodily systems operate in concert to maintain a relatively constant internal environment, or milieu intérieur.5 These bodily systems would also join together to effect a return to a constancy of the milieu intérieur even after major disruptions to an organism. Thus, Bernard’s view at the end of his career was that higher animals are in a close and informed relationship with the external world, and the relative constancy of the milieu intérieur results from moment-to-moment adjustments in various physiological systems.6

Key Points

Walter B. Cannon expanded upon Claude Bernard’s concept of the milieu intérieur and introduced the concept of homeostasis. He recognized that stressful stimuli could disrupt the constancy of the internal environment and he demonstrated that central control of epinephrine secretion from the adrenal medulla was important in reestablishing homeostatic balance.

The fight-or-flight response was a term coined by Cannon to describe the activation of an organism when exposed to a conspecific or a predator. The physiological changes in these situations, including epinephrine release into the circulation, enhance survival by increasing the delivery of oxygen and glucose to skeletal muscles and brain at the expense of the viscera and skin.

Cannon’s investigations into “voodoo death” in primitive societies revealed his broad interests in behavioral sciences and the scientific rigor of his approach. He hypothesized that voodoo death resulted in hyperactivity of the adrenal medulla, which resulted in life-threatening changes in cardiac function. Later studies by Curt P. Richter using an animal model of sudden death suggested that the mechanism was more likely associated with increases in vagal drive to the heart.

Cannon challenged the prevailing theory of emotions, the James-Lange theory, in a paper in the American Journal of Psychology in 1927. The Cannon-Bard theory of emotions, which drew on research by Cannon and his student, Philip Bard, focused attention on the hypothalamus and thalamus as critical brain areas for generating emotions and their associated peripheral physiological changes.

Cannon’s publications continue to serve as a strong foundation for contemporary studies of stress. In particular, his work on homeostasis, the fight-or-flight response, and the emergency functions of the adrenal medulla are still widely referenced by researchers.

As Cannon came into the picture, these major disruptions to an organism were expanded to include stressful stimuli. Cannon built directly upon Bernard’s theory by introducing the concept of homeostasis, with the central nervous system playing a critical role in maintaining the constancy of the internal environment. A key component of this homeostatic balance was the central control of the adrenal medulla and the sympathetic nerves and the secretion of epinephrine. As Goldstein7 has noted, Cannon was mistaken on several critical details relating to the sympathetic nervous system and the adrenal medulla but was largely correct on the bigger picture. For example, Cannon8 argued that the sympathetic nervous system and the adrenal medulla were a single functional unit that employed the same chemical messenger, epinephrine. The chemical arsenal of the sympathetic nerves was expanded, Cannon thought, through the conversion of epinephrine into two other substances, sympathin E (excitation) and sympathin I (inhibition).9,10 It was not until immediately after World War II that von Euler11 provided definitive evidence that norepinephrine was the neurotransmitter released from sympathetic nerve endings, not epinephrine. It was later still that a host of investigators revealed the two broad classes of adrenergic receptors, alpha- and beta- and their subclasses.12

PHYSIOLOGY

Body function requires a stable internal environment, described by Claude Bernard as the “milieu intérieur,” in spite of a changing outside world. Homeostasis, a state of balance, is made possible by negative feedback control systems. Complex neural and hormonal regulatory systems provide control and integration of body functions. Physicians describe “normal” values for vital signs—blood pressure of 120/80 mm Hg, pulse of 72 beats/min, respiration rate of 14 breaths/min. These “normal” vital sign values reflect a body in homeostatic balance.

A stable milieu interior also requires a balance between intake and output. Intake and production will increase the amount of a compound in the body. Excretion and consumption will decrease the amount of a compound in the body. Body fluid and electrolyte composition is regulated about a set point, which involves both control of ingestion and control of excretion. Any changes in ingestion must be compensated by changes in excretion, or the body is out of balance.

Life is not always about homeostasis and balance. The body must also adapt to changing requirements, such as during exercise. Now the normal resting values are physiologically inappropriate, since an increase in muscle blood flow, cardiac output, and respiratory rate are necessary to support the increased metabolic demands associated with physical activity. Physiology is the study of adaptive adjustments to new challenges.

Life is a state of constant change. The physiology of the body alters as we age. An infant is not a small adult, and the physiology of an octogenarian is different from that of an adolescent. Chapter 16 provides a concise summary of physiologic changes in each sex across the life span.

Finally, physiology makes sense. As a student, you need to look for the organizing principles in your study of the body. There are more details and variations than can be memorized. However, if you focus on the organizing principles, the details fall into a logical sequence. Look for the big picture first—it is always correct. The details and complex interactions all support the big picture.

Homeostasis

Much of any organism's physiology aims at homeostasis, or constancy in its ‘internal environment’ (Bernard's milieu intérieur), as to variables like temperature, blood pressure, and blood acidity, osmolarity, nutrient content, and so on. Still, many functions are not directly homeostatic (vision, locomotion), while others are not so at all (growth, reproduction). The latter aim to upset an equilibrium, not to preserve one. Not surprisingly, then, while many disorders do disrupt internal equilibrium, others, such as deafness, quadriplegia, or sterility, do not mark homeostatic failures.

Introduction

In early studies of physiological processes, French physician and physiologist Claude Bernard (1813–78) coined the phrase milieu intérieur when he wrote that “the stability of the internal environment [the milieu intérieur] is the condition for the free and independent life.” Based upon that concept, American physiologist Walter Bradford Cannon (1871–1945) coined the concept of homeostasis (Cannon, 1932), under which living beings have developed mechanisms to keep their physiological parameters within strict limits. However, Russian physiologist Mrosovsky (1990) reexamined the concept of homeostasis in his book “Rheostasis: The Physiology of Change,” in which he posited that instead of maintaining the constancy of their internal environment or having effective mechanisms to preclude changes, living organisms exhibit physiological mechanisms that cope with changes in regulated levels, which those organisms use to face environmental changes. Mrosovsky termed those mechanisms “rheostasis.”

Fish are singular examples of how changes in environmental factors operate throughout a living organism’s life cycle. For instance, aquatic organisms must cope with differences in temperature, oxygen concentration, water osmolarity, and other environmental factors all through their lives. Therefore, it is important to understand how aquatic animals attain allostasis, the process whereby internal stability—that is, homeostasis—through physiological or behavioral change is maintained, or adapt to the (environmental) changes through rheostasis (Wikelski and Cooke, 2006). The basis for triggering these physiological processes is encoded in the genetic makeup of populations. Dobzhansky and Wallace (1953) elegantly expressed the importance of genetic variability to physiological processes, stating verbatim that “Adaptation to a variety of environments is accomplished in two ways. First, most species and populations are polymorphic and consist of a variety of genotypes optimally adapted to different aspects and sequences of environments. Secondly, individuals respond to environmental changes by physiological and structural modifications. Modifications evoked by environmental variations recurrent in the environment of the species almost always tend to increase the probability of survival and reproduction of the organism. The organism adjusts itself to recurrent environmental changes in such a way that its functioning continues unimpaired; it is said to be homeostatic.”

The core of knowledge on the physiology of Neotropical fish was positively impacted by contributions from the Brazilian scientist Dr. Carlos Chagas Filho, who studied electrogenesis in the electric eel, Electrophorus electricus (Albe-Fessard et al., 1951; Chagas et al., 1953). Brazilian zoologist and biologist Dr. Rodolpho T.W.G. von Ihering studied fish reproduction and set the basis for the reproductive manipulation of Neotropical rheophilic fish, that is, fish living in flowing waters. At the International Congress of Physiology in the former USSR in 1935, Ihering and colleagues presented studies that demonstrated complete control of the spawning process of rheophilic fish by injecting pituitary extract (von Ihering et al., 1935; von Ihering and Azevedo, 1936; von Ihering, 1937). Artificial propagation allowed the development of the aquaculture of migratory Neotropical species, such as the characins pacu Piaractus mesopotamicus, tambaqui Colossoma macropomum, the siluriform surubim Pseudoplatystoma corruscans, and many other species, allowing mass fingerling production in confinement.

The seminal advance in genetics was the elucidation of base pairing and the double-helix structure of DNA by Watson and Crick (1953), a milestone enabling the understanding of how genes encode proteins and control physiological processes from the cell to the whole organism level. During the 50 years following Watson and Crick’s landmark publication, the previously separate fields—physiology and genetics—converged to elucidate the pathways underlying the regulation of gene expression, homeostasis, organism-environment interactions, and the determination of phenotype.

Fish are extraordinary vertebrate models for integrative studies of genetics and physiology. Freshwater fish inhabit diverse ecosystems and habitats, from streams at high elevation to lakes, floodplains, and rivers running through different latitudes and climatic zones to the depths of ocean trenches. Ray-finned fish comprise approximately half the diversity of all vertebrates, with about 33,000 named species (Nelson, 2006; Froese and Pauly, 2018); remarkably, around 15,000 species live in freshwater environments (IUCN, 2018). In Neotropical freshwater ecosystems, ichthyodiversity accounts for > 7000 species, with a significant number that are important as genetic resources supporting regional nutrition and income (Hilsdorf and Hallerman, 2017). The capacity of physiological adaptation that Neotropical fish have developed through evolution is shown across the many different environments throughout the Amazon watershed. These environments harbor striking physical (including water quality), chemical, and biological heterogeneity with a wide range of morphological and physiological adaptations driving the impressive diversity of freshwater fish (Val et al., 1996).

Diverse topics on the physiology of Neotropical fish are yet to be investigated. For instance, the physiological genomic mechanisms underlying the rheophilic reproductive cycle in the wild—and in confinement—are poorly understood. What are the genes involved? What are the environmental triggers, and how are they transduced into gene expression and physiological adaptation? Better understanding of the interplay of genetic and physiological processes can be applied to understand adaptation at a mechanistic level, to genetically improve rheophilic species for aquaculture, and to better sustain management of wild populations impacted by anthropogenic disturbances such as overfishing, pollution, and damming of rivers for hydropower generation.

Fish have been an important source of food throughout human history, first from fisheries and later from aquaculture. The current scenario has not changed, except for the massive scale of capture from commercial fisheries (Worm et al., 2006), the growth of world aquaculture (FAO, 2016), and in some areas of aquaculture, the increase in productivity from the use of superior, selectively bred strains (Gjedrem and Robinson, 2014). The genetic and physiological processes underlying fishery-induced evolution (the adaptive responses of wild fish stocks under constant fishing pressure) and the adaptation of cultured stocks to aquaculture (Hutchings and Fraser, 2008) are still to be fully unraveled. In recent years, novel molecular technologies, particularly next-generation sequencing (NGS), have hastened advances in genetic and physiological studies of nonmodel organisms, unlocking the organismal “black box” to address the role of physiology in the mechanisms translating genetic into phenotypic variation. This chapter introduces and discusses linkages between genetics and physiology as applied to fish farming and genetic resource conservation, first by addressing the importance of genetic diversity to the management of wild populations and the domestication and genetic improvement of aquaculture species. That is followed by a discussion on how new molecular technologies can improve the understanding and management of genetic resources of finfish species as well as the molecular bases of the fish reproductive cycle, mainly concerning rheophilic species. Finally, we explore chromosome set manipulation and gene transfer technologies as tools for investigating physiological processes in fish.

B Regulation of Life-Sustaining Activities

During the latter half of the nineteenth century, the work of Claude Bernard had demonstrated that the internal environment (i.e. milieu interieur) was maintained in a balanced state. According to Bernard, “The balance of chemicals between the tissues of the body is what determines health”. Clearly, the idea of health as an expression of balance remained in the picture even as science was becoming the dominant approach to understanding health and disease. More recently, Golub has concluded that “the biology of complexity will cause us to return to understanding that health really is a form of internal balance”, a view that is further emphasized by Esther Sternberg in her book The Balance Within: the Science Connecting Health and Emotions.

The early twentieth century also saw developments in understanding the endocrine glands and the nervous system. The study of the nervous system had been progressing in parallel to that of infectious disease. The first empirical demonstration of brain control over a vital function for life was the discovery of the respiratory center in the medulla oblongata (brainstem) by Jean-César Legallois in 1806. However, observations dating back to the mid-sixteenth century and again repeated by Thomas Willis in 1664 indicated that there was a group of nerves that affected the movement of the heart. These connections were thought, as had been previously theorized by Galen, to permit physiological “sympathy”, that is, functional unity or harmonious communication between internal organs involved in the circulation and respiration. In 1732, Jacobus Winslow introduced the notion of the “great sympathetic nerves”, which he believed controlled the viscera. By 1845, Ernest Heinrich Weber and Eduard Friedrich Weber had shown that stimulation of one of these nerves (the vagus nerve) could stop the heart, whereas stimulation of the other nerves accelerated the heart rate. These observations led Walter H. Gaskill in 1886 to the conclusion that the “involuntary system” was composed of two antagonistic components. John Newport Langley in 1898 named this system the autonomic nervous system (ANS) and referred to its antagonistic components as the sympathetic and parasympathetic branches.

The word hormone, with Greek roots meaning “to arouse”, was first used in 1905 by Ernest Henry Starling in the lecture “The Chemical Correlation of the Function of the Body”. An understanding of the powerful influence of endocrine gland secretions had been steadily growing since the 1830s. By the mid-1940s, many hormones had been chemically characterized and were thought to exert their effects by acting through receptor molecules. The role of higher order brain centers had become the focus of investigation as well. Walter Cannon concluded that the hypothalamus regulated ANS responses directed toward mobilizing bodily resources and preserving life under challenging conditions. A direct connection between the hypothalamus and the ANS was first demonstrated in 1930 by John Beattie, G.R. Brow, and C.L.H. Long. Stimulation of this pathway accelerated heart rate, mobilized the body’s energy reserve (i.e. increased glucose in the blood), and raised core body temperature (i.e. produced fever). Regulation of pituitary hormone release by the hypothalamus was eventually demonstrated in the late 1960s.

From the end of the nineteenth century to the beginning of the twentieth century, Ivan Pavlov was conducting experiments that demonstrated that visceral responses (e.g. salivation and gastric motility) could be elicited by neutral stimuli (e.g. sound of a bell) through a process of temporal pairing of the neutral stimulus with a natural stimulus (e.g. food) for eliciting such a response, a process that has come to be known as classical conditioning. Also during the first half of the twentieth century, psychosomatic medicine gained prominence through the writings of Franz Alexander and Helen Flanders Dunbar as a medical specialty concerned with bodily disorders thought to arise from psychological disturbances.

Thus, the twentieth century arrived as scientists were beginning to understand how the body protected itself and maintained an internal balance through the actions of multiple tissues coordinated by the nervous system in response to both external and internal stimuli, including those originating within the mind. Even then there were some observers such as C.H. Hughes who in 1894 was eager to put this understanding into practice: “We are approaching an era when the whole patient is to be treated no more only as a part or organ solely… In estimating the causal concomitants and sequences of his diseases, we consider the whole man in his psycho-neuro-physical relations”. In more recent times, George Engel has persuasively argued for the need to adopt a biopsychosocial model in healthcare.

Historical Contributions to Stress Concepts

Modern concepts of regulatory biology may be traced to Claude Bernard (1813–78), who pioneered the doctrine of a constancy of the milieu interieur. Walter Cannon (1871–1945) further promoted and broadened the concept of physiologic organization and regulations, especially in his 1929 report on homeostasis. That original concept referred to an ideal setting of effectors controlling the milieu interieur. However, modern concepts of homeostasis infer the occurrence of different settings of the effectors as well as the accumulation of stress impacts or allostatic load on the physiological control mechanisms. The paradigm of allostatic load proposes that stress mediators have protective as well as damaging effects on the organism. The accumulation and overexposure of the body to stresses can promote adverse effects on various systems by the mediators.

In the next decade, Hans Selye (1907–82) developed experimental (rodent) models of generalized stress reactions to noxious agents. He demonstrated opposite changes in the thymus (atrophy) and adrenals (hypertrophy) as part of the organism's responses to injuries and chemical intoxications. Those experiments revealed counterregulatory relations between the hypertrophy of adrenal glands and involution of lymphatic tissues, which he originally considered to be nonspecific.

In 1946, Selye published his synthetic theory of the general adaptation syndrome and diseases of adaptation. Relative adrenal insufficiency was proposed to be a contributory factor in stress-related or immunologically mediated diseases. Selye's research and that of others indicated that the adrenal glands are closely connected with the organism's resistance to noxious stimuli or stresses.

In humans, adrenal gland enlargement was recognized to result from a wide variety of conditions, including those of increased physiological demands (pregnancy, cold exposure, exercise, and low oxygen tension), hypermetabolic disturbances (hyperthyroidism, and excessive insulin administration), infections, burns, and other shock-producing states as well as multiple toxic drugs. The concept of stress reactions became recognized largely under Selye's influence. His theory offered a unifying mechanism to interpret complex sets of metabolic, psychoneurophysiological, immunological, and other adaptive changes that characterized responses to a wide variety of noxious or perturbing stimuli.

The above-mentioned and other concepts of stress biology will be related to selected examples of rheumatic disorders. Human stress responses are profoundly complex, but their diverse impacts may be inferred to contribute to symptoms, physiopathogenesis, or outcomes of particular rheumatic disorders.