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Biomedical subjects

Patrick Y Lee

Publications and source records attributed to Patrick Y Lee.

At least 19 recordsLinked to original sources
PubMed2006

Peripheral arterial disease: a manifestation of evolutionary dislocation and feed-forward dysfunction.

Peripheral arterial disease in the legs represents a subset of atherosclerosis that manifests a particularly sinister profile. A predominance of sympathetic activity in the periphery favors the development of neurogenic atherosclerosis. Atherosclerosis may then produce flow derangements and decreased physical activity that serves to escalate sympathetic bias in a vicious cycle. Restoration of normal flow in peripheral arterial disease may not only produce local benefit due to improved perfusion, but also represent a gateway to correcting many systemic conditions that may at first glance appear unrelated but share a common etiology of autonomic dysfunction, such as gout, acute coronary syndromes, stroke, sleep apnea, arrhythmias, depression, erectile dysfunction, inflammation, hypercoagulability, sleep disorders, bowel dysfunction, renal failure, and aging.

Atherosclerosis↗
PubMed2006

A paradigm for viewing biologic systems as scale-free networks based on energy efficiency: implications for present therapies and the future of evolution.

A network constitutes an abstract description of the relationships among entities, respectively termed links and nodes. If a power law describes the probability distribution of the number of links per node, the network is said to be scale-free. Scale-free networks feature link clustering around certain hubs based on preferential attachments that emerge due either to merit or legacy. Biologic systems ranging from sub-atomic to ecosystems represent scale-free networks in which energy efficiency forms the basis of preferential attachments. This paradigm engenders a novel scale-free network theory of evolution based on energy efficiency. As environmental flux induces fitness dislocations and compels a new meritocracy, new merit-based hubs emerge, previously merit-based hubs become legacy hubs, and network recalibration occurs to achieve system optimization. To date, Darwinian evolution, characterized by innovation sampling, variation, and selection through filtered termination, has enabled biologic progress through optimization of energy efficiency. However, as humans remodel their environment, increasing the level of unanticipated fitness dislocations and inducing evolutionary stress, the tendency of networks to exhibit inertia and retain legacy hubs engender maladaptations. Many modern diseases may fundamentally derive from these evolutionary displacements. Death itself may constitute a programmed adaptation, terminating individuals who represent legacy hubs and recalibrating the network. As memes replace genes as the basis of innovation, death itself has become a legacy hub. Post-Darwinian evolution may favor indefinite persistence to optimize energy efficiency. We describe strategies to reprogram or decommission legacy hubs that participate in human disease and death.

Animals↗
PubMed2006

Efficient inefficiency: biochemical "junk" may represent molecular bridesmaids awaiting emergent function as a buffer against environmental fluctuation.

The biochemical function of many parts of the genome, transcriptome, proteome, and interactome remain largely unknown. We propose that portions of these fundamental building blocks of life have no current biochemical function per se. Rather, sections of these "omes" may contribute to an inventory of biochemical parts and circuits that participate in the development of emergent functions. Low fidelity deoxyribonucleic acid replication, transcription, translation, and post-translational modification all represent potential mechanisms to produce an inventory of parts. Stochastic processes that influence the conformations of ribonucleic acid molecules and proteins may also contribute to potential biochemical inventory. Some components of the biochemical inventory may enable future adaptations, some may produce disease, and some may remain useless. The function of many of these components await discovery, not by science, but by evolution. While carrying such purposeless biochemical units may appear to dilute fitness by exacting a thermodynamic cost, we argue that net fitness becomes enhanced when considering the value for potential future innovations. One can envision components that intermingle, interact, and act out mock pathways, but in most cases remain molecular bridesmaids. Given sufficiently low thermodynamic cost, such stochastic cycling may persist until a markedly advantageous or cataclysmically disadvantageous trait emerges. Maladaptive screening and utilization of inventory content can lead to disease phenotypes, a process buffered and regulated in part by the heat shock protein and stress response network. Whereas failure of the ubiquitin pathway to recycle misfolded proteins has become increasingly recognized as a source of disease, protein misfolding may itself represent one step in a process that maximizes functional innovation through increasing proteomic diversity. Fractal correlates of these processes occur at the organizational level of cells and organisms. That the abnormal accumulation of units induces local collapse may serve to limit the extension of damage to the greater system at large. The immune and cognitive systems that selectively sample and prune environmental content may serve as additional portals for innovation.

Adaptation, Physiological↗
PubMed2006

Osteoarthritis: an example of phenoptosis through autonomic dysfunction?

Phenoptosis, the programmed death of organisms akin to cellular apoptosis, constitutes a type of Darwinian selection that enhances inclusive fitness. It provides a means by which senescent and pre-senescent members can self-terminate if they have incurred sufficient cumulative stress such that their continued survival detracts from inclusive fitness. Sepsis, vascular disease, menopause, cancer, and aging all represent examples of phenoptosis at work. We previously proposed that feed-forward autonomic dysfunction fundamentally drives phenoptosis in all its guises. Accordingly, we now postulate that osteoarthritis defines a type of biomechanical phenoptosis, mediated by feed-forward autonomic dysfunction, and manifested through joint destruction associated with fitness disadvantages. Biomechanical capability plays a significant role in evolutionary fitness, and sustained joint insults such as immobility or undue biomechanical stress may serve as proxies for inferior fitness. By both hindering an individual's ability to compete for energy and increasing that individual's vulnerability to predation, feed-forward joint destruction may facilitate adaptive phenoptosis among impaired or senile members. Empirical data suggests that contrary to common belief, heavy joint use does not necessarily cause osteoarthritis, whereas immobility and neuropathy can predispose to the condition. From a Darwinian perspective, another process mediated by sympathetic activity, the alarm cry of attacked prey, simultaneously promotes the escape of kin while attracting predators and scavengers. By effectively enabling the martyrdom of biomechanically-challenged individuals, osteoarthritis may serve to optimize system energy efficiency in a similar fashion. This framework may generalize to other situations where regenerative capacity dissipates in conjunction with maturation, typically leading to fibrosis. By allowing environmental pressure to sort the phenotypes, imperfect repair mechanisms may accelerate adaptation and optimize long-term inclusive fitness for all individuals. As the basis of competition shifts from biomechanical to cognitive skills, and as novel triggers for physical stress emerge, osteoarthritis may now represent a modern maladaptation.

Apoptosis↗
PubMed2006

Are we eating more than we think? Illegitimate signaling and xenohormesis as participants in the pathogenesis of obesity.

Resource utilization may represent a central force driving evolution. A tight link between sensing energy availability and managing energy acquisition and utilization constitutes a common feature among all organisms. While such a link was likely adaptive during prehistoric evolution, modern lifestyles may decouple perceived cues from actual energy availability so as to promote obesity in humans. A particular illegitimate signal is chronic stress, which may shift body phenotype to suit a more conservative state of energy management. In prehistoric times, such a response likely aided survival during periods of low resource availability. However, new sources of chronic stress have emerged that bear little relationship to contextual energy, which is generally abundant in the modern world. In addition, modern techniques of husbandry and agriculture can produce stress in the food chain, such that food itself can act as an illegitimate signal of chronic stress. Obese livestock and unusual fat profiles in farmed fish, meat, and eggs may reflect stress phenotypes. Consumers of stressed foods may sense those signals--a phenomenon known as xenohormesis--and assume the stressed phenotype. This maladaptive process may promote obesity by erroneously biasing hosts towards caloric accumulation in the context of energy abundance. Regional tissue accumulation of fat may indicate local tissue stress. Atherosclerosis may result from stress signals that induce sympathetic bias and regional fat accumulation in vessel adventitia. Medications such as neuroleptics and foods such as diet drinks may generate illegitimate signals by mimicking molecules used for energy management. Implications for the prevention and treatment of dysfunctions related to these derangements are discussed. New strategies for manufacturing biologics by manipulating stress conditions or controlling fatty acid attachments to proteins are envisioned.

Adipose Tissue↗
PubMed2006

Obesity and ADHD may represent different manifestations of a common environmental oversampling syndrome: a model for revealing mechanistic overlap among cognitive, metabolic, and inflammatory disorders.

Obesity and attention-deficit hyperactivity disorder (ADHD) are both increasing in prevalence. Childhood exposure to television has shown linkage to both ADHD and obesity with the former ascribed to dysfunctional cognitive hyperstimulation and the latter to altered patterns of diet and exercise. Empirical evidence has contradicted prior presumptions that the hyperactivity of ADHD would decrease the risk of obesity. Instead, obesity and ADHD demonstrate significant comorbidity. We propose that obesity and ADHD represent different manifestations of the same underlying dysfunction, a phenomenon we term environmental oversampling syndrome. Oversupply of information in the form of nutritional content and sensory content may independently predispose to both obesity and ADHD. Moreover, the pathogenic mechanisms of these conditions may overlap such that nutritional excess contributes to ADHD and cognitive hyperstimulation contributes to obesity. The overlapping effects of medications provide further evidence towards the existence of shared etiologic pathways. Metabolism and cognition may represent parallel systems of intelligence, and oversampling of content may constitute the source of parallel dysfunctions. The emerging association between psychiatric and metabolic disorders suggests a fundamental biologic link between these two systems. In addition, the immune system may represent yet another form of intelligence. The designation of syndrome X subsumes seemingly unrelated metabolic and inflammatory entities. Environmental oversampling syndrome may represent an even more inclusive concept that encompasses various metabolic, inflammatory, and behavioral conditions. Apparently disparate conditions such as insulin resistance, diabetes, hypertension, syndrome X, obesity, ADHD, depression, psychosis, sleep apnea, inflammation, autism, and schizophrenia may operate through common pathways, and treatments used exclusively for one of these conditions may prove beneficial for the others.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

Integrating systems biology and medical imaging: understanding disease distribution in the lung model.

OBJECTIVE: Many chronic diseases exhibit characteristic pulmonary distribution patterns, but the underlying biologic explanations remain elusive. On the basis of emerging evidence from systems biology, we propose that gradients of T helper immune function exist as an epiphenomenon of the hypoxic pulmonary vasoconstriction response. Regional variation of immune function may contribute to preferential distribution patterning of lung diseases. CONCLUSION: The lungs represent but one example in which the distribution of immune function throughout the body may explain disease location. This hypothetic framework can apply to diseases outside the realm of pulmonary biology and illustrates the potential benefit of integrating advances in systems biology and medical imaging.

Diagnostic Imaging↗
PubMed2005

Contrast nephropathy may be partly mediated by autonomic dysfunction: renal failure considered as a modern maladaptation of the prehistoric trauma response.

The mechanism behind iodinated radiocontrast nephropathy remains elusive. Direct oxidative damage is the prevailing hypothesis, but the apparent protective effect of iodine against oxidation contradicts this view. We propose that autonomic dysfunction participates in the pathogenesis of radiocontrast nephropathy and may account for other contrast-associated reactions previously attributed to allergy. Iodine, through its effects on thyroid function and chemoreceptor response to metabolic acidosis, may induce hyperadrenergia and consequently diminish renovascular flow and urine output. The renal response to adrenergia likely served an adaptive function during prehistoric evolution when trauma was a dominant source of hypovolemia and adrenergia, but the response may behave maladaptively today as evolutionarily nai ve triggers for adrenergia have emerged. Autonomic dysfunction can further impair renal function by deranging renovascular autoregulation and inducing oxidative reperfusion injury as a secondary phenomenon. Many other causes of acute renal failure such as drug toxicity, surgery, hospitalization, and diabetes may operate through hyperadrenergia, impaired renovascular autoregulation, and oxidative reperfusion injury. Dialysis, a volume reduction therapy for renal failure, can counterintuitively worsen renal dysfunction by exacerbating adrenergia, which may explain its association with accelerated atherosclerosis, inflammation, and cancer. Other examples of vicious cycles that perpetuate renal dysfunction may include renal artery stenosis, carotid stenosis, and atherosclerosis as well as the cardio-renal, hepato-renal, and pulmonary-renal syndromes. The benefits of hydration and bicarbonate in protecting renal function may operate in part through baroreceptor- and chemoreceptor-mediated reduction of sympathovagal ratio, respectively. New treatment paradigms for renal failure including pharmacologic and electro-mechanical therapies are envisioned based on autonomic remodeling, reduced sympathovagal ratio, and neuromodulation of pathways typically associated with trauma such as renin, angiotensin, vasopressin, and aldosterone.

Adaptation, Physiological↗
PubMed2005

A general theory of evolution based on energy efficiency: its implications for diseases.

We propose a general theory of evolution based on energy efficiency. Life represents an emergent property of energy. The earth receives energy from cosmic sources such as the sun. Biologic life can be characterized by the conversion of available energy into complex systems. Direct energy converters such as photosynthetic microorganisms and plants transform light energy into high-energy phosphate bonds that fuel biochemical work. Indirect converters such as herbivores and carnivores predominantly feed off the food chain supplied by these direct converters. Improving energy efficiency confers competitive advantage in the contest among organisms for energy. We introduce a term, return on energy (ROE), as a measure of energy efficiency. We define ROE as a ratio of the amount of energy acquired by a system to the amount of energy consumed to generate that gain. Life-death cycling represents a tactic to sample the environment for innovations that allow increases in ROE to develop over generations rather than an individual lifespan. However, the variation-selection strategem of Darwinian evolution may define a particular tactic rather than an overarching biological paradigm. A theory of evolution based on competition for energy and driven by improvements in ROE both encompasses prior notions of evolution and portends post-Darwinian mechanisms. Such processes may involve the exchange of non-genetic traits that improve ROE, as exemplified by cognitive adaptations or memes. Under these circumstances, indefinite persistence may become favored over life-death cycling, as increases in ROE may then occur more efficiently within a single lifespan rather than over multiple generations. The key to this transition may involve novel methods to address the promotion of health and cognitive plasticity. We describe the implications of this theory for human diseases.

Animals↗
PubMed2005

The dynamic range of biologic functions and variation of many environmental cues may be declining in the modern age: implications for diseases and therapeutics.

We hypothesize that declining dynamic range and variation of environmental cues may contribute to health dysfunctions, and that judicious expansion of biologic dynamic ranges may be beneficial. Three disparate examples involving the endocrine, autonomic, and musculoskeletal systems are discussed. Daytime sheltering, optical shading, and nighttime use of artificial light may reduce circadian luminal variation. The resulting melatonin alterations may contribute to systemic dysfunctions. Loss of temporal variation of other hormones may contribute to biologic dysfunctions, especially those involving the hypothalamic-pituitary axis. Reduced variation of physical exertion, environmental stressors, and thermal gradients that characterize modern lifestyles may reduce the autonomic dynamic range resulting in lowered heart rate variability and a myriad of systemic dysfunctions. The health benefits of activities such as exercise, meditation, acupuncture, coitus, and laughter may operate through increasing autonomic variability. Reduced physical exertion also accounts for declining dynamic range of musculoskeletal function. The resulting muscle atrophy, fat infiltration, and sarcomere shortening may not only have deleterious local effects, but may also be involved in systemic metabolic dysfunctions such as insulin resistance. The extent to which our endogenous systems rely on environmental variation for self-tuning and the impact that under-utilization of compensatory mechanisms has on biologic function are not well understood. Modern therapeutic approaches generally result in reversion to the mean of physiologic functions and may buffer against variation. For example, beta-blockers are given to reduce adrenergic excess, insulin to treat insulin insufficiency, serotonin-reuptake inhibitors for depression, and refractive lenses for myopia. By undermining the demand for native compensatory functions, such therapeutic strategies may actually impair future ability to respond to biologic disequilibria. Generalizing from these observations, we anticipate benefits of therapeutic and lifestyle approaches that expand, rather than reduce, the dynamic range of many biologic experiences.

Animals↗
PubMed2005

"Starve a fever and feed a cold": feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance.

Anorexia is a common symptom accompanying infections, but the teleology of the phenomenon remains unexplained. We hypothesize that anorexia may represent a prehistoric behavioral adaptation to fight infection by maintaining T helper (Th)2 bias, which is particularly vital in fighting bacterial pathogens. Specifically, we propose that anorexia may avert the reduction of Th2/Th1 ratio by preventing feeding-induced neurohormonal and vagal output from the gut. Emerging evidence suggests that the vagal and neurohormonal output of the gut during feeding promotes Th1 function, which is desirable in fighting viral infections. Since fever may be an adaptation to fight bacteria and "colds" are generally viral in origin, the adage "starve a fever and feed a cold" may reflect a sensible behavioral strategy to tilt autonomic and Th balance in directions that are optimal for fighting the particular type of infection. The ability to modulate T helper balance through the neurohormonal and autonomic axis by adjusting food intake may be the mechanism behind other unexplained clinical observations such as the improved outcomes of ICU patients after enteric versus parenteric feedings. Compared to the prehistoric period when bacterial infection was commonplace, the anorexic response may be less adaptive today when viruses and cancers have become common triggers of anorexia. By promoting host anorexia, cachexia, and insomnia, cancers and viruses can deter behaviors such as digestion and sleep that would raise vagal and Th1 activity against tumors and viruses. Hydration and sleep, unexplained but widely accepted recommendations for flu patients, may also work by promoting vagal and Th1 functions. Modulating feeding, hydration, and sleep may prove beneficial in treating other conditions associated with abnormal autonomic and Th balance.

Adaptation, Physiological↗
PubMed2005

A new mechanism for diverticular diseases: aging-related vagal withdrawal.

It is widely believed that diverticulosis, a common condition among the elderly, results from repeated colonic barotrauma related to low dietary fiber and low stool bulk. Recent evidence has challenged the dietary-barotrauma hypothesis. We propose an alternative hypothesis that diverticulosis may be attributable to colonic smooth muscle dysfunction that results from vagal attrition associated with aging. We previously proposed that broad aging-related attrition of autonomic nerves may unmask intrinsic sympathetic bias of end-organs, leading to the compendium of familiar conditions associated with senility. Unexplained cholinergic hypersensitivity and receptor over-expression in bowel affected by diverticulosis have recently been observed. These findings are highly suggestive of a compensatory response to loss of vagal innervation. The resulting autonomic dysregulation may induce bowel smooth muscle dysfunction, setting the stage for diverticula formation. Thus, diverticular bowel disease may be a manifestation of the aging-related systemic vagal withdrawal. The framework may extend to diverticula formation in other parts of the gastrointestinal and genitourinary tracts. For instance, aging-related vagal attrition may represent the common upstream mechanism that induces both sphincter of Oddi dysfunction and peri-ampullary duodenal diverticula, conditions that frequently occur together. Novel approaches to preventing and treating diverticular diseases by promoting vagal activity are proposed including the electrical or pharmacologic modulation of the autonomic system.

Aging↗
PubMed2005

Clinical benefits of hydration and volume expansion in a wide range of illnesses may be attributable to reduction of sympatho-vagal ratio.

Hydration and volume expansion regimens are widely thought to offer symptomatic benefit in many human ailments. Many varied theories for the phenomenon exists such as decreased blood viscocity in cardiac disease, dilution of toxins in cancer, and cleansing effect on airways in asthma. While it is plausible that disparate mechanisms are involved in different conditions, we propose an alternative, unifying hypothesis that many of the clinical benefits of hydration and volume expansion are partly related to reduced sympatho-vagal ratio. Hypovolemia triggers baroreceptor-mediated sympathetic response and neurohormonal activation to promote fluid retention. Emerging evidence suggests that many diseases including cardiovascular, neurologic, gastrointestinal, metabolic, inflammatory, thrombotic, viral, and oncologic conditions are manifestations of abnormal sympathetic bias and associated T helper 2 bias. Hypovolemia-induced sympathetic activation, especially if baroreceptor dysfunction is involved, can worsen these conditions. Hydration and volume expansion may lower sympatho-vagal ratio, thereby tempering a wide variety of clinical conditions linked directly or indirectly to adrenergia including, but not limited to, acute coronary syndromes, asthma, cancer, and stroke. Interestingly, isotonic or hypertonic hydration, rather than a low-salt diet, may be a counterintuitive potential strategy to treat some cases of hypertension associated with dehydration and autonomic dysfunction. In contrast to the putative causal relationship between them, perhaps hypertension and end-organ damage represent independent consequences of dysfunctional sympathetic and neurohormonal activation. Venipuncture enables faster volume expansion but may also be a source of sympathetic hyperactivity. Oral hydration may additionally promote vagal tone by triggering gastric distension, a benefit not offered by intravenous fluids. The empiric benefits of hydration and volume expansion portend novel methods to treat a wide range of clinical conditions through pharmacologic or electrical modulation of cardiovascular or gastrointestinal baroreceptors.

Asthma↗
PubMed2005

Can thromboembolism be the result, rather than the inciting cause, of acute vascular events such as stroke, pulmonary embolism, mesenteric ischemia, and venous thrombosis?: a maladaptation of the prehistoric trauma response.

Thromboembolism is considered the inciting cause of many vascular disorders including acute coronary syndrome (ACS), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and mesenteric ischemia. Adrenergia and inflammation are known to accompany these conditions, particularly among arterial thromboembolic disorders, but the teleologic basis of these associations remains poorly understood. We argue that thromboembolism may sometimes be the result, rather than the cause, of acute vascular events, and may be precipitated by underlying adrenergia. Thromboembolic events are most prone to occur during parts of the circadian, seasonal, lifespan, and reproductive cycles with sympathetic dominance, as well as during behavioral, exertional, physiologic, and iatrogenic activation of sympathetic stress. Molecular evidence suggests that adrenergia and inflammation can promote coagulation and lead to co-activation of the pathways. Acute vascular events that occur without angiographic evidence of occlusion suggest that some infarcts may be attributable to adrenergia alone. "Embolic" disorders may represent asynchronous systemic phenomena rather than clot migration. During acute thromboembolism, downstream tissue hypoxia can activate maladaptive self-propelling cycles of sympathetic bias, inflammation, and coagulation. The counterproductive co-activation of these pathways may reflect a maladaptive interlink forged during the primordial evolution of trauma physiology. Their rapid co-mobilization enables rapid control of hemorrhage, microbial defense, and perfusion maintenance during trauma, but the pathways may behave maladaptively in the setting of modern diseases where endothelial injury may be more often precipitated by smoking, diabetes, dyslipidemia, or hypertension. Sympathetic blockade is already employed in ACS, and beta-blockers are used as antihypertensives to prevent stroke. Our hypothesis suggests that the benefits of beta-blockers in stroke may be independent of antihypertensive effects, and that adrenergia may represent a target for managing all thromboembolic disorders, independent of anti-coagulative and thrombolytic therapies. Perhaps reducing adrenergia, rather than maintaining high cerebral perfusion pressure, may represent a counterintuitive strategy for treating stroke and for reducing reperfusion injury. Plausible mechanisms by which autonomic dysfunction may induce venous thrombosis are discussed, especially in those with baroreceptor dysfunction, immobilization, or dehydration. Unexplained hypercoagulability of cancer may also operate through tumor-induced adrenergia and inflammation.

Humans↗
PubMed2005

Paradoxical strategy for treating chronic diseases where the therapeutic effect is derived from compensatory response rather than drug effect.

Reversing chronic conditions remains an elusive goal of medicine. The modern medical paradigm based on blocking overactive pathways or augmenting deficient pathways offers symptomatic benefit, but tolerance to therapy can develop and treatment cessation can produce rebound symptoms due to compensatory mechanisms. We propose a paradoxical strategy for treating chronic conditions based on harnessing compensatory mechanisms for therapeutic benefit. Many current drugs may be repurposed for a paradoxical indication where the therapeutic effect is derived from compensatory response, rather than drug effect. For example, although exercise is associated with acute adrenergia, paradoxical downregulation of baseline sympathovagal ratio occurs as a remodeling response. For conditions that manifest chronic sympathetic bias such as cardiovascular diseases, judicious administration of adrenergic agonists may induce compensatory downregulation of baseline sympathovagal ratio. The concept may generalize to many other diseases, especially those involving pathways which exhibit strong homeostatic tendencies such as the neurologic, immune, and endocrine systems. Careful consideration of chronobiologic features is necessary to optimize dosing strategies for modulating compensatory responses, and eccentric dosing schedules, shorter-acting formulations, or pulsatile delivery may be desirable in some cases. To what extent the effect of desensitization to current therapy is mistaken for disease progression in conditions such as diabetes, myopia, depression, and hypertension warrants investigation. The merits of combining behavioral and drug therapies such as diet-insulin therapy for diabetes and exercise-beta-blockade for cardiovascular disease should be revisited since there is a risk for exacerbating the underlying dysfunction. The reduced dynamic range of various environmental experiences and the tendency to revert to the mean through medical intervention, thermoregulation, and other modern lifestyle changes may play under-recognized roles in human diseases. Perhaps alternating agonists and antagonist may exercise the entire dynamic range of pathways and improve health.

Adrenergic Agonists↗
PubMed2005

The smoking gun: many conditions associated with tobacco exposure may be attributable to paradoxical compensatory autonomic responses to nicotine.

Tobacco exposure is implicated in many illnesses such as cardiovascular disease and cancer, but the mechanisms underlying these associations are poorly understood. The mechanisms by which tobacco induces pro-sympathetic and pro-inflammatory changes also remain elusive. Some studies have attributed these changes to the direct effects of nicotine, but such findings run counter to the pro-vagal, anti-inflammatory nature of the nicotinic pathway. We hypothesize that the illnesses associated with smoking may be partly attributable to autonomic dysfunction, sympathetic bias, and T helper (Th)2 inflammation induced by a paradoxical compensatory response to intermittent nicotinic exposure. The confusion of interpreting the adrenergia and inflammation associated with nicotine as a primary response instead of a secondary compensation may be explained by the unusually rapid absorption, action, and serum elimination of nicotine. Given the fast action and clearance of nicotine, even heavy smokers spend large portions of the day and the entire night in nicotine withdrawal, at which time rebound sympathetic bias may manifest as a result of desensitization of nicotinic receptors. This may help reconcile why the features observed in smokers such as tachycardia, hypertension, inflammation, insomnia, and anxiety, which are perhaps mistakenly attributed to the direct action of nicotine, are identical to those seen during acute nicotine withdrawal after smoking cessation. On the other hand, delayed responses to cessation of smoking such as weight gain and increased heart rate variability are compatible with reduced sympathovagal ratio and resensitization of nicotinic receptors. Sympathetic bias and the associated Th2 inflammation underlie many systemic diseases. Tobacco-related cancers may be partly attributable to immunomodulatory properties of chronic nicotine exposure by dampening Th1 immunity and enabling tumoral evasion of immune surveillance. Other conditions associated with tobacco exposure may also operate through similar autonomic and immune dysfunctions. Therapeutic implications are discussed.

Anxiety↗