This month in J Lab Clin Med: Issue highlights for October 2001

Abstract

Histamine and asthmaLike many allergic disorders, asthma may be associated with high levels of histamine in the blood, and histamine is a credible contributor to airway constriction. But that may not be its only rôle. Histamine and serotonin can serve as chemical messengers between inflammatory cells, and it is possible that such an action could underlie the common presence of neutrophils and monocytes in the bronchial fluid of asthmatics, even in the absence of infection.An article in this month's issue of the Journal by Dr Hiroshi Nomura and several colleagues from the Shinshu Medical College (Matsumoto, Japan) and the Kyoto University explores one possible scenario: that histamine and/or serotonin might encourage alveolar macrophages to release chemotaxins for neutrophils or monocytes (see page 226 ).Bovine alveolar macrophages were grown in tissue culture, in the presence or absence of added serotonin or histamine. The supernatant culture medium was then tested for its ability to attract normal human neutrophils or monocytes in a microchamber adaptation of the Boyden chamber.As the hypothesis would predict, macrophages grown with either supplemental histamine or supplemental serotonin released chemotactic substances into the culture medium; the majority of the activity was attributable to a small, lipid-soluble substance (or substances). The likely identity of the major chemotaxin was leukotriene B4. That is, lipoxygenase inhibitors decreased production of the chemotaxin, leukotriene B4 antagonists blocked its activity, and assayable leukotriene B4 went up in the medium in parallel with increased chemotactic activity.The authors conclude that histamine and serotonin may promote the inflammatory component of asthma by promoting recruitment of inflammatory cells to the lung.Immune tolerance and inflammatory bowel diseaseInflammatory bowel disease is a group of autoimmune disorders characterized by immune attack on the enteric mucosa and sometimes by attack on other tissues containing antigens related to the target antigens in colonic mucosa. The treatment of these disorders includes a variety of anti-inflammatory agents delivered systemically or delivered to the mucosal surface. A more satisfying solution would be selective induction of tolerance to the target antigen(s); this possibility becomes more attractive as techniques are developed for inducing tolerance through oral exposure to antigens. Indeed, it has been possible in some experimental models of inflammatory bowel disease to ameliorate or prevent bowel injury through oral presentation of candidate proteins or tissue extracts.Dr Arunansu Dasgupta and associates from the Robert Wood Johnson Medical School asked whether oral administration of mucosal proteins would ameliorate colitis induced by the hapten trinitrobenzene sulfonic acid (TNBS), whether such tolerance would be specific to colonic mucosa, and what mediators were likely to be involved. As described beginning on page 261, they administered TNBS rectally to rats after feeding them extracts of human colon cancer cell line cells, extracts of human fibroblasts, or extracts of normal rattine enteric mucosa. Fifteen days later the rats were killed; their rectal histology was examined and some inflammatory mediators were measured.Rectal inflammation was predictably induced by the instillation of TNBS, as expected; this was severe enough that a quarter of the animals died before 15 days had elapsed. Pre-feeding with human colon cancer extract protected against the proctitis; interestingly, this protection was organ-specific but not species-specific. That is, rat colon extract was also protective, but neither human fibroblast extract nor rattine small bowel extract offered protection.To examine the mechanism of the tolerance a bit farther, the authors harvested T lymphocytes from the spleens and mesenteric lymph nodes of animals that had been fed colonic extracts. These lymphocytes were then given to animals that had not been given any extracts, and the TNSB challenge was given as before. Considerable protection was afforded by this passive lymphocyte transfer.If it were possible to induce such tolerance after the inflammation had been triggered, it could prove a useful approach to treating inflammatory bowel disease.Three generations of imbeciles: The power of an image (and this month's cover)A picture may, as the proverb says, be worth a thousand words. That may be very fine when the image adds clarity and aids understanding. It's not so fine when the picture adds a sense of legitimacy or authority to words that have little merit. An example provides this month's cover illustration, accompanied by an essay by Paul Lombardo of the Center for Biomedical Ethics at the University of Virginia (see page 282 ).In 1927 the United States Supreme Court upheld the right of individual states to mandate the sterilization on eugenic grounds of persons believed to have serious heritable deficiencies. The specific case, Buck v Bell, involved a family in which three generations of feeblemindedness were alleged; in fact, the individual assessments rested on incorrect information and false assumptions, and there was no convincing evidence of any inherited disorder. Nonetheless, a simple kindred diagram looked pretty convincing.The Supreme Court vote had only one dissenter, Justice Pierce Butler of Minnesota. He did not write a dissenting opinion and seems not to have discussed his thinking about the case in his published works. We are left to speculate: Did he see the weakness in the eugenic argument? Did he accept the argument but find forced sterilization unacceptable on libertarian grounds? Or did his religious conservatism lead him to a moral objection to eugenic sterilization independent of libertarian concerns?The Journal welcomes submissions in the areas of medical or research ethics, as well as articles bearing on the history of medicine or of biologic research. We also welcome the submission of possible cover illustrations. As the current issue shows, these two can be combined. If a brief case report or historical note has an image as a major part of its message, it may be a suitable candidate for publication as a cover illustration with a supporting essay.E-cadherin: An adhesive protein important to enteric integrity and healingThe description in the last 25 years of a large number of adhesive proteins has given a much clearer understanding of cell migration, cell-to-cell interaction, and interactions between cells and their substrata. The occupancy of the binding sites for adhesive proteins, moreover, may have a major impact on other cell functions such as growth or elaboration of secretory products.An example is described in this month's issue of the Journal, beginning on page 236. Dr Nobuyuki Moriyama and several colleagues from the Shimane Medical University, Juntendo University, and Akita University (all in Japan) explored the rôle of E-cadherin on healing of gastric mucosa. E-cadherin is already known to be important in epithelial integrity, and its expression has been reported to be weak at the margins of refractory ulcers in Crohn's disease. This could simply mean that sick cells in bad ulcers don't express this protein well, or it could be an observation of direct pathologic importance.Rat gastric mucosal cells were grown to confluence on collagen-coated culture plates. A small defect was made in the monolayer, and its restoration was monitored over time; this was done in the presence and in the absence of antibodies to E-cadherin. In the presence of the antibodies, restoration of the monolayer's integrity was delayed in a dose-dependent manner. Further suggesting that E-cadherin is important to healing, mRNA for the protein was quickly up-regulated in the cells adjacent to the “wound.” Moreover, the intensity of immunostaining for E-cadherin became more intense at the margins of the defect.These findings suggest that E-cadherin is likely to be important to the healing of defects in enteric epithelium.Why do we wear out?We have it on ancient authority that man is allotted threescore years and ten. Gains in longevity in modern times have not brought us very far beyond that standard: old people are not much older now than they were in years gone by; there are simply more of them (because there have been large gains in sanitation, nutrition, and control of childhood infectious diseases). Why is that?There are several processes involved in aging, and it's a reasonable thought that some may be “planned obsolescence” and some may be the result of imperfections in our body's ability to repair insults encountered along the way. From a Darwinian perspective, one would expect selective pressure strongly to favor features that ensure good repair during reproductive life and to have little effect on post-reproductive durability.Current thinking about the aging process is summarized for us this month by Dr H. R. Armbrecht of Saint Louis University, beginning on page 220. Histamine and asthmaLike many allergic disorders, asthma may be associated with high levels of histamine in the blood, and histamine is a credible contributor to airway constriction. But that may not be its only rôle. Histamine and serotonin can serve as chemical messengers between inflammatory cells, and it is possible that such an action could underlie the common presence of neutrophils and monocytes in the bronchial fluid of asthmatics, even in the absence of infection.An article in this month's issue of the Journal by Dr Hiroshi Nomura and several colleagues from the Shinshu Medical College (Matsumoto, Japan) and the Kyoto University explores one possible scenario: that histamine and/or serotonin might encourage alveolar macrophages to release chemotaxins for neutrophils or monocytes (see page 226 ).Bovine alveolar macrophages were grown in tissue culture, in the presence or absence of added serotonin or histamine. The supernatant culture medium was then tested for its ability to attract normal human neutrophils or monocytes in a microchamber adaptation of the Boyden chamber.As the hypothesis would predict, macrophages grown with either supplemental histamine or supplemental serotonin released chemotactic substances into the culture medium; the majority of the activity was attributable to a small, lipid-soluble substance (or substances). The likely identity of the major chemotaxin was leukotriene B4. That is, lipoxygenase inhibitors decreased production of the chemotaxin, leukotriene B4 antagonists blocked its activity, and assayable leukotriene B4 went up in the medium in parallel with increased chemotactic activity.The authors conclude that histamine and serotonin may promote the inflammatory component of asthma by promoting recruitment of inflammatory cells to the lung. Like many allergic disorders, asthma may be associated with high levels of histamine in the blood, and histamine is a credible contributor to airway constriction. But that may not be its only rôle. Histamine and serotonin can serve as chemical messengers between inflammatory cells, and it is possible that such an action could underlie the common presence of neutrophils and monocytes in the bronchial fluid of asthmatics, even in the absence of infection. An article in this month's issue of the Journal by Dr Hiroshi Nomura and several colleagues from the Shinshu Medical College (Matsumoto, Japan) and the Kyoto University explores one possible scenario: that histamine and/or serotonin might encourage alveolar macrophages to release chemotaxins for neutrophils or monocytes (see page 226 ). Bovine alveolar macrophages were grown in tissue culture, in the presence or absence of added serotonin or histamine. The supernatant culture medium was then tested for its ability to attract normal human neutrophils or monocytes in a microchamber adaptation of the Boyden chamber. As the hypothesis would predict, macrophages grown with either supplemental histamine or supplemental serotonin released chemotactic substances into the culture medium; the majority of the activity was attributable to a small, lipid-soluble substance (or substances). The likely identity of the major chemotaxin was leukotriene B4. That is, lipoxygenase inhibitors decreased production of the chemotaxin, leukotriene B4 antagonists blocked its activity, and assayable leukotriene B4 went up in the medium in parallel with increased chemotactic activity. The authors conclude that histamine and serotonin may promote the inflammatory component of asthma by promoting recruitment of inflammatory cells to the lung. Immune tolerance and inflammatory bowel diseaseInflammatory bowel disease is a group of autoimmune disorders characterized by immune attack on the enteric mucosa and sometimes by attack on other tissues containing antigens related to the target antigens in colonic mucosa. The treatment of these disorders includes a variety of anti-inflammatory agents delivered systemically or delivered to the mucosal surface. A more satisfying solution would be selective induction of tolerance to the target antigen(s); this possibility becomes more attractive as techniques are developed for inducing tolerance through oral exposure to antigens. Indeed, it has been possible in some experimental models of inflammatory bowel disease to ameliorate or prevent bowel injury through oral presentation of candidate proteins or tissue extracts.Dr Arunansu Dasgupta and associates from the Robert Wood Johnson Medical School asked whether oral administration of mucosal proteins would ameliorate colitis induced by the hapten trinitrobenzene sulfonic acid (TNBS), whether such tolerance would be specific to colonic mucosa, and what mediators were likely to be involved. As described beginning on page 261, they administered TNBS rectally to rats after feeding them extracts of human colon cancer cell line cells, extracts of human fibroblasts, or extracts of normal rattine enteric mucosa. Fifteen days later the rats were killed; their rectal histology was examined and some inflammatory mediators were measured.Rectal inflammation was predictably induced by the instillation of TNBS, as expected; this was severe enough that a quarter of the animals died before 15 days had elapsed. Pre-feeding with human colon cancer extract protected against the proctitis; interestingly, this protection was organ-specific but not species-specific. That is, rat colon extract was also protective, but neither human fibroblast extract nor rattine small bowel extract offered protection.To examine the mechanism of the tolerance a bit farther, the authors harvested T lymphocytes from the spleens and mesenteric lymph nodes of animals that had been fed colonic extracts. These lymphocytes were then given to animals that had not been given any extracts, and the TNSB challenge was given as before. Considerable protection was afforded by this passive lymphocyte transfer.If it were possible to induce such tolerance after the inflammation had been triggered, it could prove a useful approach to treating inflammatory bowel disease. Inflammatory bowel disease is a group of autoimmune disorders characterized by immune attack on the enteric mucosa and sometimes by attack on other tissues containing antigens related to the target antigens in colonic mucosa. The treatment of these disorders includes a variety of anti-inflammatory agents delivered systemically or delivered to the mucosal surface. A more satisfying solution would be selective induction of tolerance to the target antigen(s); this possibility becomes more attractive as techniques are developed for inducing tolerance through oral exposure to antigens. Indeed, it has been possible in some experimental models of inflammatory bowel disease to ameliorate or prevent bowel injury through oral presentation of candidate proteins or tissue extracts. Dr Arunansu Dasgupta and associates from the Robert Wood Johnson Medical School asked whether oral administration of mucosal proteins would ameliorate colitis induced by the hapten trinitrobenzene sulfonic acid (TNBS), whether such tolerance would be specific to colonic mucosa, and what mediators were likely to be involved. As described beginning on page 261, they administered TNBS rectally to rats after feeding them extracts of human colon cancer cell line cells, extracts of human fibroblasts, or extracts of normal rattine enteric mucosa. Fifteen days later the rats were killed; their rectal histology was examined and some inflammatory mediators were measured. Rectal inflammation was predictably induced by the instillation of TNBS, as expected; this was severe enough that a quarter of the animals died before 15 days had elapsed. Pre-feeding with human colon cancer extract protected against the proctitis; interestingly, this protection was organ-specific but not species-specific. That is, rat colon extract was also protective, but neither human fibroblast extract nor rattine small bowel extract offered protection. To examine the mechanism of the tolerance a bit farther, the authors harvested T lymphocytes from the spleens and mesenteric lymph nodes of animals that had been fed colonic extracts. These lymphocytes were then given to animals that had not been given any extracts, and the TNSB challenge was given as before. Considerable protection was afforded by this passive lymphocyte transfer. If it were possible to induce such tolerance after the inflammation had been triggered, it could prove a useful approach to treating inflammatory bowel disease. Three generations of imbeciles: The power of an image (and this month's cover)A picture may, as the proverb says, be worth a thousand words. That may be very fine when the image adds clarity and aids understanding. It's not so fine when the picture adds a sense of legitimacy or authority to words that have little merit. An example provides this month's cover illustration, accompanied by an essay by Paul Lombardo of the Center for Biomedical Ethics at the University of Virginia (see page 282 ).In 1927 the United States Supreme Court upheld the right of individual states to mandate the sterilization on eugenic grounds of persons believed to have serious heritable deficiencies. The specific case, Buck v Bell, involved a family in which three generations of feeblemindedness were alleged; in fact, the individual assessments rested on incorrect information and false assumptions, and there was no convincing evidence of any inherited disorder. Nonetheless, a simple kindred diagram looked pretty convincing.The Supreme Court vote had only one dissenter, Justice Pierce Butler of Minnesota. He did not write a dissenting opinion and seems not to have discussed his thinking about the case in his published works. We are left to speculate: Did he see the weakness in the eugenic argument? Did he accept the argument but find forced sterilization unacceptable on libertarian grounds? Or did his religious conservatism lead him to a moral objection to eugenic sterilization independent of libertarian concerns?The Journal welcomes submissions in the areas of medical or research ethics, as well as articles bearing on the history of medicine or of biologic research. We also welcome the submission of possible cover illustrations. As the current issue shows, these two can be combined. If a brief case report or historical note has an image as a major part of its message, it may be a suitable candidate for publication as a cover illustration with a supporting essay. A picture may, as the proverb says, be worth a thousand words. That may be very fine when the image adds clarity and aids understanding. It's not so fine when the picture adds a sense of legitimacy or authority to words that have little merit. An example provides this month's cover illustration, accompanied by an essay by Paul Lombardo of the Center for Biomedical Ethics at the University of Virginia (see page 282 ). In 1927 the United States Supreme Court upheld the right of individual states to mandate the sterilization on eugenic grounds of persons believed to have serious heritable deficiencies. The specific case, Buck v Bell, involved a family in which three generations of feeblemindedness were alleged; in fact, the individual assessments rested on incorrect information and false assumptions, and there was no convincing evidence of any inherited disorder. Nonetheless, a simple kindred diagram looked pretty convincing. The Supreme Court vote had only one dissenter, Justice Pierce Butler of Minnesota. He did not write a dissenting opinion and seems not to have discussed his thinking about the case in his published works. We are left to speculate: Did he see the weakness in the eugenic argument? Did he accept the argument but find forced sterilization unacceptable on libertarian grounds? Or did his religious conservatism lead him to a moral objection to eugenic sterilization independent of libertarian concerns? The Journal welcomes submissions in the areas of medical or research ethics, as well as articles bearing on the history of medicine or of biologic research. We also welcome the submission of possible cover illustrations. As the current issue shows, these two can be combined. If a brief case report or historical note has an image as a major part of its message, it may be a suitable candidate for publication as a cover illustration with a supporting essay. E-cadherin: An adhesive protein important to enteric integrity and healingThe description in the last 25 years of a large number of adhesive proteins has given a much clearer understanding of cell migration, cell-to-cell interaction, and interactions between cells and their substrata. The occupancy of the binding sites for adhesive proteins, moreover, may have a major impact on other cell functions such as growth or elaboration of secretory products.An example is described in this month's issue of the Journal, beginning on page 236. Dr Nobuyuki Moriyama and several colleagues from the Shimane Medical University, Juntendo University, and Akita University (all in Japan) explored the rôle of E-cadherin on healing of gastric mucosa. E-cadherin is already known to be important in epithelial integrity, and its expression has been reported to be weak at the margins of refractory ulcers in Crohn's disease. This could simply mean that sick cells in bad ulcers don't express this protein well, or it could be an observation of direct pathologic importance.Rat gastric mucosal cells were grown to confluence on collagen-coated culture plates. A small defect was made in the monolayer, and its restoration was monitored over time; this was done in the presence and in the absence of antibodies to E-cadherin. In the presence of the antibodies, restoration of the monolayer's integrity was delayed in a dose-dependent manner. Further suggesting that E-cadherin is important to healing, mRNA for the protein was quickly up-regulated in the cells adjacent to the “wound.” Moreover, the intensity of immunostaining for E-cadherin became more intense at the margins of the defect.These findings suggest that E-cadherin is likely to be important to the healing of defects in enteric epithelium. The description in the last 25 years of a large number of adhesive proteins has given a much clearer understanding of cell migration, cell-to-cell interaction, and interactions between cells and their substrata. The occupancy of the binding sites for adhesive proteins, moreover, may have a major impact on other cell functions such as growth or elaboration of secretory products. An example is described in this month's issue of the Journal, beginning on page 236. Dr Nobuyuki Moriyama and several colleagues from the Shimane Medical University, Juntendo University, and Akita University (all in Japan) explored the rôle of E-cadherin on healing of gastric mucosa. E-cadherin is already known to be important in epithelial integrity, and its expression has been reported to be weak at the margins of refractory ulcers in Crohn's disease. This could simply mean that sick cells in bad ulcers don't express this protein well, or it could be an observation of direct pathologic importance. Rat gastric mucosal cells were grown to confluence on collagen-coated culture plates. A small defect was made in the monolayer, and its restoration was monitored over time; this was done in the presence and in the absence of antibodies to E-cadherin. In the presence of the antibodies, restoration of the monolayer's integrity was delayed in a dose-dependent manner. Further suggesting that E-cadherin is important to healing, mRNA for the protein was quickly up-regulated in the cells adjacent to the “wound.” Moreover, the intensity of immunostaining for E-cadherin became more intense at the margins of the defect. These findings suggest that E-cadherin is likely to be important to the healing of defects in enteric epithelium. Why do we wear out?We have it on ancient authority that man is allotted threescore years and ten. Gains in longevity in modern times have not brought us very far beyond that standard: old people are not much older now than they were in years gone by; there are simply more of them (because there have been large gains in sanitation, nutrition, and control of childhood infectious diseases). Why is that?There are several processes involved in aging, and it's a reasonable thought that some may be “planned obsolescence” and some may be the result of imperfections in our body's ability to repair insults encountered along the way. From a Darwinian perspective, one would expect selective pressure strongly to favor features that ensure good repair during reproductive life and to have little effect on post-reproductive durability.Current thinking about the aging process is summarized for us this month by Dr H. R. Armbrecht of Saint Louis University, beginning on page 220. We have it on ancient authority that man is allotted threescore years and ten. Gains in longevity in modern times have not brought us very far beyond that standard: old people are not much older now than they were in years gone by; there are simply more of them (because there have been large gains in sanitation, nutrition, and control of childhood infectious diseases). Why is that? There are several processes involved in aging, and it's a reasonable thought that some may be “planned obsolescence” and some may be the result of imperfections in our body's ability to repair insults encountered along the way. From a Darwinian perspective, one would expect selective pressure strongly to favor features that ensure good repair during reproductive life and to have little effect on post-reproductive durability. Current thinking about the aging process is summarized for us this month by Dr H. R. Armbrecht of Saint Louis University, beginning on page 220. Histamine stimulates alveolar macrophages to release neutrophil and monocyte chemotactic activityThe Journal of Laboratory and Clinical MedicineVol. 138Issue 4PreviewHistamine and serotonin are important inflammatory mediators in the pathophysiology of asthma, and asthmatic patients have higher plasma histamine and serotonin levels than non-asthmatic control subjects. Alveolar macrophages (AMs) synthesize and secrete a large number of substances that play a key role in acute and chronic inflammation including asthma. We postulated that AMs might release chemotactic activity for neutrophils and monocytes in response to histamine or serotonin. To test this hypothesis, bovine AMs were cultured, and the supernatant fluids were evaluated for neutrophil chemotactic activity (NCA) and monocyte chemotactic activity (MCA) by a blind well chamber technique. Full-Text PDF Colon epithelial cellular protein induces oral tolerance in the experimental model of colitis by trinitrobenzene sulfonic acidThe Journal of Laboratory and Clinical MedicineVol. 138Issue 4PreviewRectal administration of trinitrobenzene sulfonic acid (TNBS) produces chronic co-litis in experimental animals. However, the role of epithelial cellular protein(s) in this model is unknown. We examined whether oral tolerance can be induced in this model with colon epithelial cell proteins and whether it is organ specific. Rats were fed five times with extracts of LS-180 human colon cancer cells or HT 1080 human fibroblast cells. Syngeneic normal rat colon or small intestinal extracts were fed to separate groups of rats. Full-Text PDF Carrie Buck's pedigreeThe Journal of Laboratory and Clinical MedicineVol. 138Issue 4PreviewFew opinions in United States Supreme Court history are as notorious as the decision delivered by Justice Oliver Wendell Holmes in the 1927 case of Buck v Bell.1 That lawsuit, which challenged a Virginia eugenics law allowing the state-mandated sexual sterilization of epileptics, the mentally retarded, and others judged “socially inadequate,” concluded with Holmes declaring, “Three generations of imbeciles are enough.” The Buck decision is unique in the history of medical jurisprudence as the only occasion in which the United States Supreme Court has endorsed surgery on unwilling patients as a tool of state policy. Full-Text PDF E-cadherin is essential for gastric epithelial restitution in vitro: A study using the normal rat gastric mucosal cell line RGM1The Journal of Laboratory and Clinical MedicineVol. 138Issue 4PreviewThe proliferation and migration of epithelial cells appear to have important roles in intercellular adhesion and the regeneration of gastric mucosal lesions. However, the role of E-cadherin, an important intercellular adhesion molecule, in restitution after gastric mucosal damage is unknown. This study was designed to investigate the possible role of E-cadherin in the regeneration of gastric mucosal lesions. Artificial small wounds were made in an RGM1 confluent monolayer sheet, and the healing process was monitored with or without the presence of different concentrations of anti-E-cadherin antibodies. Full-Text PDF The biology of agingThe Journal of Laboratory and Clinical MedicineVol. 138Issue 4Previewhe question of why we age is fascinating from many perspectives. From a biologic perspective, what are the processes that convert healthy adults into frail older ones with an increased burden of disease? From an evolutionary perspective, what role does aging play in the overall survival and evolution of a species? From a philosophic/spiritual perspective, why do we age at all? In the last few years there has been an explosive growth in our understanding of the biology of aging. These new findings shed some light on these questions. Full-Text PDF