Correspondence Address:
Kezhong Zhang
Center for Molecular Medicine and Genetics, Wayne State University, School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201
USA

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Stress and stress response are hot research topics since they are intrinsically linked to the development of modern human common diseases; in another word, environmental disease.[1] As intensive research efforts on these topics have been emerging, it is important to recapitulate the basic principle and involvement of stress and stress response in health and disease. In this editorial insight review, I will discuss two points: (1) the basic principle of stressor, stress response, and homeostasis and (2) the complex system of multiple stressors in health and disease.

Clinical observations and biomedical research confirmed that the most common and life-threatening diseases, such as cardiovascular disease, diabetes, neurodegenerative disease, and cancer, are associated with environmental stressors. Stress responses are critically involved in the initiation and progression of the diseases. However, to lay people and even some researchers, the definition and basic principle of stressor and stress response in health and diseases are not as clear as we assumed. From a broad view, many cellular or physiological processes, such as immune cell activation upon infection, apoptosis, autophagy, heat shock response, hormone response, and energy fluctuations, are all “stress responses.” The environmental, physiological, or pathological conditions that trigger stress responses are considered as “stressors.” In all the stress response model systems, there are three basic elements: stressor, stress response, and homeostasis (also called “adaptation” or “system remodeling”) [Figure 1]. In response to a stressor, which could be environmental change, alteration of endogenous hormone or cytokine, or energy fluctuation that challenges the status quo of physiological processes or system stability, a homeostatic system (cell and organism) could raise a homeostatic overload.[2],[3] To deal with the stressor, the system initiates stress responses, a condition also called “reactive homeostasis.” Stress responses, through a variety of approaches or pathways, such as hormone responses, inflammation, endoplasmic reticulum (ER) stress response, and oxidative stress response, lead to transcriptional and translational reprogramming in order to re-establish cellular homeostasis. Stress response helps the system to adapt to the stress conditions triggered by stressors. During this process, the homeostatic system is remodeled and upgraded to a new version by stress responses [Figure 1]. This scenario occurs within a normal reactive scope, and the stress response or stress signaling will not lead to pathogenesis under this condition. Instead, it helps cells or organisms to survive from the stress condition. Like the “good stress” exercise, appropriate levels of stress make the cell or organism stronger or healthier. Therefore, the primary function of stress responses is protective and survival promoting. However, when stress gets prolonged or too severe for the system to handle, it then causes homeostatic failure and system instability [Figure 1]. Under this condition, stressors, through stress responses, will promote pathogenesis, facilitating many types of diseases.{Figure 1}

An important issue concerning the involvement of stressor or stress response in health and disease is the pathophysiological significance of multiple stressors in a complex system. People easily assume that the combination of two or multiple stressors can make the thing worse, compared to a single stressor. In another word, does the “two-hit” or “multiple-hit” hypothesis, which explains the synergic relationship between the hereditary and nonhereditary forms of oncogenic factors in causing cancers,[4] applies to the pathophysiological effects of multiple stressors? Emerging evidences suggest that this may not be the case. In a homeostatic system involving multiple environmental stressors, when two “evils” (stressors) encounter, they may not necessarily work together to make “the thing” worse. One typical example is that air pollution can counteract the effect of high-fat or “Western-style” diet on causing metabolic syndrome as revealed by a recent study.[5] It was established that inhalation exposure to fine airborne particulate matter PM2.5, the major toxic component of polluted air, causes hepatic ER stress, oxidative stress, and inflammation, leading to nonalcoholic steatohepatitis (NASH)-like phenotype and hepatic insulin resistance in mice under the normal chow diet.[6],[7],[8],[9] As the high-fat diet represents a common health risk factor associated with the development of metabolic disorders, it was attempted to assume that airborne PM2.5 pollution can synergize with a high-fat diet to promote metabolic symptoms. However, it appears that inhalation exposure to PM2.5 exerts an unexpected “beneficial” effect on counteracting fatty liver phenotype induced by a high-fat diet.[5] PM2.5 exposure relieves lipid accumulation in the livers of mice under the high-fat diet, which is achieved by inducing hepatic lipophagy, a lysosomal degradative pathway that eliminates lipid contents under energy-demanding or stress conditions.[5],[10] This counteractive stress model shifts our understanding of the “two hits” hypothesis in NASH, in which two stressors or insults act together to facilitate pathogenesis.[11] In this complex system involving air pollution and overnutrient stress, the environmental stressor, PM2.5 exposure, mitigates the effect of the metabolic stressor, the high-fat diet, in driving pathogenesis. This scenario raised an interesting question: whether the individuals with NASH or associated metabolic syndrome resulted from high-fat or “Western-style” diet under clean air environments can gain “therapeutic benefits” by living in the areas under high levels of ambient PM2.5, such as China and India, for a designated time period?[5],[12] This seems silly, but it is intriguing in the context of complex effects of multiple stressors.

Another example of counteractive effects of multiple stressors is the inverse association between cancer and Alzheimer's disease.[13],[14] The results from a large-scale community-based cohort study, the Framingham Heart Study of the USA, indicated that cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer. Interestingly, the risk of Alzheimer's disease was lowest in survivors of smoking-related cancers.[13] The inverse association between cancer and Alzheimer's disease is similar to the case observed with Parkinson's disease and cancer.[15],[16] A mechanistic basis underlying the inverse association between cancer and neurodegenerative diseases may be explained by the shared biological signaling pathways that result in opposite end points in cancer and neurodegeneration:[17],[18],[19] uncontrolled cell proliferation is detrimental for cancer, but beneficial for Alzheimer's or Parkinson's disease, while apoptosis is “therapeutic” for cancer, but detrimental for the neurodegenerative diseases.

In the past decades, stress or stress response in health and disease is a fast-growing research field. A huge number of publications in the topic of stress and disease are emerging – most of them have been addressing the detrimental or pathological aspects of stressors or stress responses. This may lead to a misleading view that stress or stress response is in general bad or harmful to the well-being of human health. However, the real situation is that the primary role of stress response is protective and survival promoting. Precise understanding of the dogma and basic principle of stressor, stress response, and homeostasis is very important for researchers to interpret their experimental results. In addition, it should be borne in mind that effects of multiple stressors in complex homeostatic systems may not be simply synergic or additive. The functional impact of multiple stressors may not be one direction. The pathophysiological outcome of stressor or stress response needs to be carefully evaluated case by case.

Acknowledgment

The research in Dr. Zhang's laboratory was partially supported by the National Institutes of Health grants DK090313 and ES017829 (to KZ), AR066634 (to KZ), and American Heart Association grants 0635423Z and 09GRNT2280479 (to KZ).

References