Background Most of the studies on traditional Chinese medicine (TCM) ‘spleen’ deficiency syndrome in the recent 30 years were conducted only on the basis of single functional index, neglecting the study on the pathophysiologic internal relationship between spleen deficiency syndrome and gastric diseases in modern medicine. But it was at the subcellular molecular biological level that we explored the pathophysiologic basis of classification of spleen deficiency in chronic gastritis by detecting the bioactive substances in gastric mucosa nuclei and mitochondria.
Methods By means of optical microscope, scanning electron microscope (SEM), transmission electron microscopy (TEM) and histochemical staining, we conducted histopathological, subcellular ultrastructural analysis and nuclei and mitochondrial ultrastructural analysis of gastric mucosa of 188 spleen deficiency patients and of 42 voluntary blood donors. At the same time, bioactive substances were measured by means of X-ray energy dispersive analysis system (EDAX) image analysis system, radioimmunoassay method and chemiluminescence method.
Results The content of cAMP, superoxide dismutase (SOD), Zn and Cu in gastric mucosa, and the content of Zn and Cu in mitochondria decreased progressively in order of groups: healthy control (HC), spleen Qi deficiency without organic lesion (F-SQD), spleen Yang deficiency without organic lesion (F-SyangD), disease without symptoms group, spleen Qi deficiency with organic lesion (G-SQD), spleen Yang deficiency with organic lesion (G-SyangD), spleen Yin deficiency (SyinD) and spleen deficiency with Qi stagnation (SDQS), chronic spleen deficiency gastritis (CSG) and chronic atrophic gastritis (CAG); decreased in order of HC, intestinal metaplasia (IM)Ⅰa， IMⅠb， IMⅡa and IMⅡb, P<0.05. The content of DNA, Zn and Cu in nuclei progressively increased in order mentioned above, P<0.05.
Discussion In traditional Chinese medicine (TCM), spleen and stomach are functionally in one unit, cooperating with other organs such as liver, gallbladder, large intestine and small intestine. Spleen and stomach play the roles designated as digestion, absorption, nutrition metabolism by modern medicine, and affect the physiological activities of other systems such as immunity, haematopoiesis and muscular activity. Weakness of spleen and stomach result in hypofunction of digestion, absorption and metabolism, thus the decrease of internal nutrients and failure of general functional activities, disturbance of immunity system and eventually organic degeneration. Taking care of spleen and stomach is an important step for body strengthening, disease prevention and cure.
When gastric mucosa is damaged by noxious substances or ischemia, metabolism of Zn and Cu become disordered and enzyme systems are disturbed. Zn is an essential component of over a hundred enzymes and thus participates in the metabolism of sugars, lipids, proteins, nuclei acid and vitamins. Zinc also contends for mercaptan to inhibit free radical reaction. Similarly, Cu is an essential component of over 30 proteins and enzymes, and it influences cellular respiration and division. When the levels of Zn or Cu in organism decline the synthesis and activity of SOD will be inhibited. Because of the ubiquity of NADPH and the catalytic function of xanthine oxidase, oxygen free radicals far beyond the clearing ability of SOD are produced. Oxygen free radicals react by peroxidation with unsaturated fatty acid of inner and outer mitochondrial membranes to produce lipid hyperoxide (LPO), therefore level of LPO in serum will rise.The inner and outer mitochondrial membranes will accordingly be damaged, resulting in the decrease and disarray of mitochondrial cristae, the change of the ratio of mitochondrial ventricle diameter to cavity diameter and eventfully apoptosis. Mitochondria are sites of the tricarboxylic acid cycle. If the mitochondria degrade, circulating ATP will decrease, causing cellular debility due to inadequate energy supply, structural atrophy, decrease of gastric acid secretion and even necrosis. Zinc and copper are essential for nuclear protein synthesis (including DNA duplication) and mitochondrial energy metabolism. When nuclei take in more Zn and Cu, the protein synthesis is brisk, and nuclear division and hyperplasia are accelerated, thus increasing the chance of gene mutation. As the second messenger, cAMP regulates some vital activities and once the quantity of cyclic nucleoside phosphate in nuclei changes abnormally, a pathological state of the organism will occur (CSG, CAG and IM). The quantitative changes of cAMP result in changes of cellular metabolism, immunity and vegetative functions. The decrease of cyclic nucleoside phosphate, especially cAMP, results in the inhibition of sympathetic nerve (including purinergic nerve) function, and relative hyperfunction of para-sympathetic nerve function. As a result, digestive tract symptoms occur: such as distension of epigastrium, loose stool, involuntary drooling, poor appetite and pale enlarged tongue with tooth marks.Through influencing lymphocyte me-tabolism, the quantitative changes of Zn and cAMP in turn influence cell respiration and differentiation, inhibit lymphocyte transformation and decline 3H-TdRLCT level.
Although spleen deficiency can manifest itself as a lesion of gastric mucosa with or without symptoms, it arises from deficiencies of Zn and Cu in the nuclei and mitochondria of epithelial gastric mucosa. The clinical phenomenon of “disease without symptoms” occurs in some patients, with lesions of gastric mucosa, because of such factors as genetic diathesis and compensation.The quantitative changes of gastric mucosa cAMP, SOD, Zn and Cu, of mitochondrial Zn and Cu, and of nuclei DNA, Zn and Cu are not only the physical base on which the lesion of gastric mucosa tissue structure occurs, but also the physical base on which spleen deficiency is classified.
The general characteristics of spleen deficiency are low levels of blood cAMP and cytoimmunity, as well as high levels of serum LPO. Nuclear metabolism of spleen deficiency with Qi stagnation is vigorous while mitochondrial energy metabolism is weak. The degree of cellular division and proliferation is greater than that of cellular differentiation and maturation. Nuclear metabolism and mitochondrial energy metabolism of spleen Qi deficiency become weak simultaneously. Cells are aging and becoming senile prematurely.Such clinical phenomena signs of gastric cancer are: decreasing content of Zn and Cu in gastric mucosa, spleen deficiency with Qi stagnation, abnormally increasing the content of DNA in nuclei, contracting intestinal metaplasia Ⅱb subset in gastric mucosa, increasing and deforming nuclei, and increasing degeneration rate of mitochondria. We should pay close attention to these phenomena for early diagnosis of gastric cancer. We examined, by SEM, gastric mucosa of nonfocal region in remaining stomach of gastrectomy patients. Although these gastric mucosa looked normal to the naked eye, we still found that background lesions such as focal superficial gastritis, focal atrophic gastritis and micro-ulcer really existed. The results proved that chronic gastric diseases (duodenal antral region ulcer, gastric ulcer, etc) are diseases of the whole stomach, not just isolated lesions.Therefore, we point out that the danger of the gastric precancerous condition of the remaining stomach (the background lesion) must be taken into consideration while surgical treatment for chronic gastric diseases is being conducted. “In principal, nonmalignant gastric disease patients-noncanceration or no tendency to canceration―without serious complications should avoid surgical operations. Even if an operation is necessary for such patients, we must be careful to choose the way of operation and have a good grasp of the resection extent, and then treat them with internal medicine of integrated traditional Chinese and western medicine to prevent remaining stomach diseases.”
Reviewing the two thousand years of developmental history of TCM theories, we found some prototypes of modern scientific philosophy such as “macroscopic balance”, “fuzzy logic” and “submacroscopic adjustment” were around long ago, the typical result of which is the “syndrome and viscera-state doctrine”. However, TCM theories have been isolated and conservative for long time and poor at identification. Besides, “fuzzy logic” used to be applied in a too simple way with little importance attached to qualitative, localization and quantitative factors. Consequently, the criteria for distinguishing some symptoms are not distinctive and even obscure. In order to modernize TCM, we should refrain from following the stereotyped thinking, and draw on ALL the useful knowledge of modern science and technology to establish a medical system which has a integrations of syndrome and disease.
Conclusions The quantitative changes of gastric mucosal cAMP, SOD, Zn, Cu, of mitochondrial Zn, Cu and of nuclear DNA, Zn and Cu are not only the substance base on which the lesion of gastric mucosa tissue structure occurs, but also the substance base on which spleen deficiency is classified. G-SQD and G-SyangD were more likely to be found in low-grade or middle-grade CSG and CAG, while SyinD and SDQS in middle-grade or high-grade CSG, CAG and IMⅡb.
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