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Kinins Are Generated in Nasal Secretions during Natural Rhinovirus Colds David Proud, Robert M. Naclerio, Jack M. Gwaltney, and J. Owen Hendley
From the Department of Medicine, Division of Clinical Immunology and Depanment of Otolaryngology, Johns Hopkins University, Baltimore, Maryland, and Department of Medicine and Pediatrics, University of Virginia, Charlottesville
The common cold is the most frequently experienced respiratory illness in humans. While many virus types can induce cold symptoms, at least 30% of the colds contracted annually can be attributed to rhinovirus infections [1]. Although it is uniformly accepted that viral infection is the crucial initiating step in the pathogenesis of a cold, the sequence of events between infection and the manifestation of symptoms remains unknown. Since rhinovirus infections, unlike influenza infections, result in no obvious changes in the morphology or integrity of the nasal epithelium [2], symptoms are unlikely to be due to cytotoxic effects of the virus. An alternative hypothesis is that viral infection triggers the generation of inflammatory mediators and that symptomatology results from the actions of such mediators. Support for this concept was recently provided from a study of experimentally induced rhinovirus colds in which inflammatory mediators were measured in nasal secretions obtained by lavage [3]. Although no changes were observed during experimentally
induced colds in the concentrations of histamine in nasal lavages, striking increases were seen in the concentrations of the potent vasoactive peptides, bradykinin and lysylbradykinin, during symptomatic rhinovirus infections. Elevated kinin levels were associated with increases in vascular permeability, as indicated by elevated levels of albumin in lavages, and with an influx in neutrophils. Kinin levels were riot increased in sham-infected controls or during asymptomatic infections and a significant correlation was observed between symptom scores and increases in the concentrations of kinins in nasal lavages [3]. Kinins have previously been shown to be generated during allergic reactions in both the upper and lower airways [4, 5]. These data, together with the known pharmacologic actions of kinins, have led to the suggestion that these potent autacoids may playa role in the pathogenesis of a variety of inflammatory diseases of the airways [6]. Clearly, the observations made during experimentally induced rhinovirus infections raise the possibility that kinins may also contribute to the symptomatology of rhinovirus colds. Further support for this possibility was provided by the recent demonstration that nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat [7]. Ifkinins are to be considered potential mediators of the symptoms of the common cold, however, it is important to extend our observations beyond an experimental model to the natural disease. We prospectively studied the levels of inflammatory mediators in nasal lavages from noninfected, asymptomatic subjects compared with the mediator content in lavages of the same subjects during naturally occurring rhinovirus colds.
Received 7 February 1989; revised 31 July 1989. Informed consent was obtained from the study subjects and the guidelines of the University of Virginia Committee on Clinical Investigation for human experimentation were followed in the conduct of clinical research. The experimental protocol was approved by the Human Investigation Committee, University of Virginia. This is publication 759 from the O'Neill Laboratories, Good Samaritan Hospital. Supported in part by grants-in-aid from Richardson, Vicks, Inc., and by grants HL-32272 and HL-37199 from the National Heart, Lung and Blood Institute, and NS-22488 from the National Institute of Neurological and Communicative Disorders and Stroke. Reprints and correspondence: Dr. David Proud, Johns Hopkins University School of Medicine, Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, MD 21239.
Subjects and Methods
The Journal of Infectious Diseases 1990;161:120-123 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6101-0024$01.00
Population. One hundred workers from the Eastern Regional Office, State Farm Insurance Companies, were recruited for the in-
Downloaded from http://jid.oxfordjournals.org/ at Columbia University Libraries on October 18, 2014
A prospective study compared the levelsof inflammatory mediators in nasal lavages from noninfected, asymptomatic subjects with the mediator content of lavages from the same subjects during naturally occurring rhinovirus colds. Samples were obtained from 16subjects who experienced natural colds that could be attributed to rhinovirus infections. Kinin levels during symptomatic colds were significantly elevated (P < .01) compared with those measured when the subjects were noninfected and asymptomatic. Increases in kinins correlated with increased vascular permeability, as monitored by increased concentrations of albumin in lavages. In contrast, histamine levels in nasal lavages were not increased during symptomatic infections, suggesting that mast cell and basophil activation does not occur during rhinovirus colds. These data confirm and extend observations made during experimentally induced rhinovirus infections to the natural disease and are consistent with the hypothesis that kinins may playa role in the pathogenesis of symptomatic rhinovirus infections.
1ID 1990;161 (January)
Concise Communications
thus the rate of shedding of rhinovirus by asymptomatic persons is low (2%) [9]. A total of 636 specimens were processed for mediator measurements and stored at -70°C until all virologic testing was completed. Of these specimens, 96 from 16 individuals with proven rhinovirus colds were tested for mediators. Viral isolation and identification. Before freezing, aliquots of respiratory secretions were tested for the presence of rhinovirus by inoculation of 0.3 rnl per tube into three screw-eappedtubes ofMRC-5 human embryonic lung fibroblasts, using a standard method of culture [10]. Rhinoviruses were identified by their characteristic cytopathic effect in cell culture and by the demonstration of their acid sensitivity [10]. Sixteen rhinoviruses were recovered from 53 persons with acute respiratory illnesses. Mediator assays. Kinins were measured using a competitive radioimmunoassay capable of detecting 20 pg of bradykinin/rnl [4]. The antibody used does not distinguish, on a molar basis, between bradykinin, Iysylbradykinin, and methionyllysylbradykinin. Intraand interassay coefficients of variation were
Kinins Are Generated in Nasal Secretions during Natural Rhinovirus Colds David Proud, Robert M. Naclerio, Jack M. Gwaltney, and J. Owen Hendley
From the Department of Medicine, Division of Clinical Immunology and Depanment of Otolaryngology, Johns Hopkins University, Baltimore, Maryland, and Department of Medicine and Pediatrics, University of Virginia, Charlottesville
The common cold is the most frequently experienced respiratory illness in humans. While many virus types can induce cold symptoms, at least 30% of the colds contracted annually can be attributed to rhinovirus infections [1]. Although it is uniformly accepted that viral infection is the crucial initiating step in the pathogenesis of a cold, the sequence of events between infection and the manifestation of symptoms remains unknown. Since rhinovirus infections, unlike influenza infections, result in no obvious changes in the morphology or integrity of the nasal epithelium [2], symptoms are unlikely to be due to cytotoxic effects of the virus. An alternative hypothesis is that viral infection triggers the generation of inflammatory mediators and that symptomatology results from the actions of such mediators. Support for this concept was recently provided from a study of experimentally induced rhinovirus colds in which inflammatory mediators were measured in nasal secretions obtained by lavage [3]. Although no changes were observed during experimentally
induced colds in the concentrations of histamine in nasal lavages, striking increases were seen in the concentrations of the potent vasoactive peptides, bradykinin and lysylbradykinin, during symptomatic rhinovirus infections. Elevated kinin levels were associated with increases in vascular permeability, as indicated by elevated levels of albumin in lavages, and with an influx in neutrophils. Kinin levels were riot increased in sham-infected controls or during asymptomatic infections and a significant correlation was observed between symptom scores and increases in the concentrations of kinins in nasal lavages [3]. Kinins have previously been shown to be generated during allergic reactions in both the upper and lower airways [4, 5]. These data, together with the known pharmacologic actions of kinins, have led to the suggestion that these potent autacoids may playa role in the pathogenesis of a variety of inflammatory diseases of the airways [6]. Clearly, the observations made during experimentally induced rhinovirus infections raise the possibility that kinins may also contribute to the symptomatology of rhinovirus colds. Further support for this possibility was provided by the recent demonstration that nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat [7]. Ifkinins are to be considered potential mediators of the symptoms of the common cold, however, it is important to extend our observations beyond an experimental model to the natural disease. We prospectively studied the levels of inflammatory mediators in nasal lavages from noninfected, asymptomatic subjects compared with the mediator content in lavages of the same subjects during naturally occurring rhinovirus colds.
Received 7 February 1989; revised 31 July 1989. Informed consent was obtained from the study subjects and the guidelines of the University of Virginia Committee on Clinical Investigation for human experimentation were followed in the conduct of clinical research. The experimental protocol was approved by the Human Investigation Committee, University of Virginia. This is publication 759 from the O'Neill Laboratories, Good Samaritan Hospital. Supported in part by grants-in-aid from Richardson, Vicks, Inc., and by grants HL-32272 and HL-37199 from the National Heart, Lung and Blood Institute, and NS-22488 from the National Institute of Neurological and Communicative Disorders and Stroke. Reprints and correspondence: Dr. David Proud, Johns Hopkins University School of Medicine, Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, MD 21239.
Subjects and Methods
The Journal of Infectious Diseases 1990;161:120-123 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6101-0024$01.00
Population. One hundred workers from the Eastern Regional Office, State Farm Insurance Companies, were recruited for the in-
Downloaded from http://jid.oxfordjournals.org/ at Columbia University Libraries on October 18, 2014
A prospective study compared the levelsof inflammatory mediators in nasal lavages from noninfected, asymptomatic subjects with the mediator content of lavages from the same subjects during naturally occurring rhinovirus colds. Samples were obtained from 16subjects who experienced natural colds that could be attributed to rhinovirus infections. Kinin levels during symptomatic colds were significantly elevated (P < .01) compared with those measured when the subjects were noninfected and asymptomatic. Increases in kinins correlated with increased vascular permeability, as monitored by increased concentrations of albumin in lavages. In contrast, histamine levels in nasal lavages were not increased during symptomatic infections, suggesting that mast cell and basophil activation does not occur during rhinovirus colds. These data confirm and extend observations made during experimentally induced rhinovirus infections to the natural disease and are consistent with the hypothesis that kinins may playa role in the pathogenesis of symptomatic rhinovirus infections.
1ID 1990;161 (January)
Concise Communications
thus the rate of shedding of rhinovirus by asymptomatic persons is low (2%) [9]. A total of 636 specimens were processed for mediator measurements and stored at -70°C until all virologic testing was completed. Of these specimens, 96 from 16 individuals with proven rhinovirus colds were tested for mediators. Viral isolation and identification. Before freezing, aliquots of respiratory secretions were tested for the presence of rhinovirus by inoculation of 0.3 rnl per tube into three screw-eappedtubes ofMRC-5 human embryonic lung fibroblasts, using a standard method of culture [10]. Rhinoviruses were identified by their characteristic cytopathic effect in cell culture and by the demonstration of their acid sensitivity [10]. Sixteen rhinoviruses were recovered from 53 persons with acute respiratory illnesses. Mediator assays. Kinins were measured using a competitive radioimmunoassay capable of detecting 20 pg of bradykinin/rnl [4]. The antibody used does not distinguish, on a molar basis, between bradykinin, Iysylbradykinin, and methionyllysylbradykinin. Intraand interassay coefficients of variation were
