Dendritic cells with antigen-presenting capability reside in airway epithelium, lung parenchyma, and visceral pleura.

In this study, we identified a population of dendritic cells (DC) that exists throughout human and mouse pulmonary tissues, including the trachea, bronchi, alveoli, and visceral pleura. In human tissue, these DC were shown to be positive for HLA-DR and T200 antigens. In the mouse, the DC expressed not only Ia and the T200 antigen, but also Fc-IgG and C3bi receptors. Unlike alveolar macrophages, the DC were negative for nonspecific esterase staining and shared ultrastructural similarities with the DC described by Steinman (1), and with Langerhans' cells, even though they did not contain Birbeck granules. We were able to demonstrate that mouse pulmonary DC function in antigen presentation, as observed with the other DC. Thus, the respiratory tract contains DC that are capable of functioning in antigen presentation and that may be important in pulmonary immune responses.

Vasoactive intestinal peptide in human nasal mucosa.

Vasoactive intestinal peptide (VIP), which is present with acetylcholine in parasympathetic nerve fibers, may have important regulatory functions in mucous membranes. The potential roles for VIP in human nasal mucosa were studied using an integrated approach. The VIP content of human nasal mucosa was determined to be 2.84 +/- 0.47 pmol/g wet weight (n = 8) by RIA. VIP-immunoreactive nerve fibers were found to be most concentrated in submucosal glands adjacent to serous and mucous cells. 125I-VIP binding sites were located on submucosal glands, epithelial cells, and arterioles. In short-term explant culture, VIP stimulated lactoferrin release from serous cells but did not stimulate [3H]glucosamine-labeled respiratory glycoconjugate secretion. Methacholine was more potent than VIP, and methacholine stimulated both lactoferrin and respiratory glycoconjugate release. The addition of VIP plus methacholine to explants resulted in additive increases in lactoferrin release. Based upon the autoradiographic distribution of 125I-VIP binding sites and the effects on explants, VIP derived from parasympathetic nerve fibers may function in the regulation of serous cell secretion in human nasal mucosa. VIP may also participate in the regulation of vasomotor tone.

Pathophysiology of rhinitis. Lactoferrin and lysozyme in nasal secretions.

The antimicrobial proteins lactoferrin (Lf) and lysozyme (Ly) are invariably found in nasal secretions. To investigate the cellular sources and the secretory control of these nasal proteins in vivo, 34 adult subjects underwent nasal provocation tests with methacholine (MC), histamine (H), and gustatory stimuli. Nasal lavages were collected and analyzed for total protein (TP), albumin (Alb), Lf, and Ly. MC (25 mg), H (1 mg), and gustatory stimuli (spicy foods) all increased the concentrations of TP, Alb, Lf, and Ly. However, when each protein was assessed as a percentage of TP (i.e., Alb% = Alb/TP; Lf% = Lf/TP; Ly% = Ly/TP), MC and gustatory stimuli, which both induce glandular secretion, selectively augmented Lf% and Ly% without changing Alb%, while H, which primarily increases vascular permeability, increased Alb% without significantly affecting Lf% or Ly%. Gel electrophoresis and immunoblotting analysis of nasal secretions demonstrated both Lf and Ly in cholinergically induced secretions. Furthermore, histochemical analyses of nasal turbinate tissue revealed Lf and Ly colocalization within the serous cells of submucosal glands, providing evidence that both proteins are strictly glandular products within the nasal mucosa. Therefore, both Lf and Ly are produced and secreted from the glands, and their secretion may be pharmacologically regulated in attempts to improve host defenses.

Selective defect in myeloid cell lactoferrin gene expression in neutrophil specific granule deficiency.

Neutrophil specific granule deficiency (SGD) is a congenital disorder associated with an impaired inflammatory response and a deficiency of several granule proteins. The underlying abnormality causing the deficiencies is unknown. We examined mRNA transcription and protein synthesis of two neutrophil granule proteins, lactoferrin and myeloperoxidase in SGD. Metabolically labeled SGD nucleated marrow cells produced normal amounts of myeloperoxidase, but there was no detectable synthesis of lactoferrin. Transcripts of the expected size for lactoferrin were detectable in the nucleated marrow cells of two SGD patients, but were markedly diminished in abundance when compared with normal nucleated marrow cell RNA. Because lactoferrin is secreted by the glandular epithelia of several tissues, we also assessed lactoferrin in the nasal secretions of one SGD patient by ELISA and immunoblotting. Nasal secretory lactoferrin was the same molecular weight as neutrophil lactoferrin and was secreted in normal amounts. From these data, we conclude that lactoferrin deficiency in SGD neutrophils is tissue specific and is secondary to an abnormality of RNA production. We speculate that the deficiency of several granule proteins is due to a common defect in regulation of transcription that is responsible for the abnormal myeloid differentiation seen in SGD patients.

Analysis of plasma histamine levels in patients with mast cell disorders.

PURPOSE: The use of plasma histamine determinations as a screening tool to distinguish patients with recurrent unexplained anaphylaxis, flushing, or both from those with mastocytosis has never been evaluated. This retrospective study was designed to determine if plasma histamine levels can be used as a screening test. PATIENTS AND METHODS: Values of plasma histamine levels, measured using a sensitive radioenzymatic assay, from 41 patients with mastocytosis, 26 patients with recurrent unexplained anaphylaxis, and 76 normal subjects were statistically analyzed to determine diagnostic usefulness and accuracy. Patients with mastocytosis were subdivided into four smaller groups on the basis of clinical and histopathologic findings: (1) isolated urticaria pigmentosa, (2) indolent systemic mastocytosis, (3) mastocytosis with dysmyelopoiesis, and (4) lymphadenopathic mastocytosis with eosinophilia. RESULTS: The distribution of plasma histamine values among patients with unexplained anaphylaxis strongly resembled that among the normal subjects (p greater than 0.50, Smirnov test), whereas patients with mastocytosis tended to show moderate to marked elevations above the upper limit of normal (617 pg/mL). The geometric mean plasma histamine levels in mastocytosis subgroups 2, 3, and 4 were found to be quite similar (1,085, 1,976, and 1,433 pg/mL; p greater than 0.50, F-test); moreover, each mean level was significantly greater than those of the normal subjects and of patients with unexplained anaphylaxis (p less than 0.01, Scheffé multiple comparison test). Analysis of the 27 sets of plasma histamine values collected on patients with indolent systemic mastocytosis revealed that the earliest value observed fell below 617 pg/mL in eight patients (30%). A similar analysis applied to the two earlier values indicated that both values would fall below 617 pg/mL in 9% of the patients. Data in four patients with mastocytosis demonstrated a diurnal variation in plasma histamine, with the highest values observed in the early morning (approximately 2:00 A.M.) and the lowest values in the afternoon (approximately 2:00 P.M.). CONCLUSIONS: We conclude that, on average, patients with mastocytosis have elevated plasma histamine levels, whereas patients with unexplained anaphylaxis have plasma histamine levels within the normal range during asymptomatic periods; that plasma histamine levels in patients with mastocytosis exhibit a diurnal variation; and that plasma histamine determinations alone are not useful to screen patients for mastocytosis.

Neutrophil attractant/activation protein-1 (NAP-1) causes human basophil histamine release.

Basophils from five of six human donors released histamine in response to neutrophil attractant/activation protein-1 (NAP-1). Histamine release by this protein was concentration-dependent over the range of 3 x 10(-7) M to 4 x 10(-6) M. At 4 x 10(-6) M, the mean agonist-induced release was 16 +/- 3% (SEM) of total basophil histamine. For the same basophil preparations, release by anti-IgE was 35 +/- 6%. The chemotactic protein did not cause release of histamine from basophils at 0 degrees C or in the presence of 10 mM EDTA. The time-course of histamine release was rapid; release was 43% of maximal after 30 s and maximal after 1 min of incubation. Thus, in addition to its previously characterized neutrophil chemotactic and activating properties, this protein activates human basophils.

Relationships between permeable vessels, nerves, and mast cells in rat cutaneous neurogenic inflammation.

Electrical stimulation of rat sensory nerves produces cutaneous vasodilation and plasma protein extravasation, a phenomenon termed "neurogenic inflammation". Rat skin on the dorsum of the paw developed neurogenic inflammation after electrical stimulation of the saphenous nerve. In tissue sections, the extravasation of the supravital dye monastral blue B identified permeable vessels. Mast cells were identified by toluidine blue stain. Permeable vessels were significantly more dense in the superficial 120 microns of the dermis than in the deeper dermis, whereas mast cells were significantly more frequent in the deeper dermis. The relationships between nociceptive sensory nerve fibers, permeable vessels, and mast cells were examined by indirect immunohistochemistry for calcitonin gene-related peptide (CGRP), neurokinin A (NKA), and substance P (SP). CGRP-, NKA-, and SP-containing nerves densely innervated the superficial dermis and appeared to innervate the vessels that became permeable during neurogenic inflammation. In contrast, mast cells were not associated with either permeable vessels or nerve fibers. These data suggest that electrical stimulation of rat sensory nerves produces vascular permeability by inducing the release of neuropeptides that may directly stimulate the superficial vascular bed. Mast cells may not be involved in this stage of cutaneous neurogenic inflammation in rat skin.

Effects of capsaicin desensitization on nasal mucosal secretion in guinea pigs in vivo.

Capsaicin-sensitive mechanisms may contribute to histamine's effects on guinea pig nasal mucosal secretion in vivo. Histamine nasal provocations were performed, secretions were collected, and the following variables were measured: total protein (marker of all secretory processes), alkaline phosphatase (marker of glandular secretion), and albumin (marker of vascular permeability, epithelial permeability, and glandular transport). By challenging only one nostril (ipsilateral), the contralateral responses to these challenges were examined and the nature of "nasonasal" reflexes was determined. Histamine increased albumin and alkaline phosphatase concentrations in lavage fluid on the ipsilateral and contralateral sides. The alkaline phosphatase secretion was reduced by atropine. Capsaicin induced dose-dependent albumin exudation. To determine the roles of capsaicin-sensitive sensory nerves, one nostril was desensitized by topical application of capsaicin to one nostril in increasing doses daily for 5 wk. This led to 1) ablation of all secretory responses to capsaicin, 2) ablation of histamine-induced alkaline phosphatase and total protein secretion, 3) blunted histamine-induced albumin exudation on the desensitized side, and 4) ablation of histamine-induced contralateral reflex-mediated protein secretion. These results indicate that capsaicin stimulates vascular responses, probably by stimulating nociceptive nerve axon responses. Histamine induces vascular responses and albumin exudation by both capsaicin-sensitive sensory neuron axon responses and direct effects on vessels. Histamine stimulates glandular secretion through a capsaicin-sensitive afferent/cholinergic efferent reflex.

Neuropeptide Y is a vasoconstrictor in human nasal mucosa.

Neuropeptide Y (NPY) is a neurotransmitter in sympathetic nerve fibers in human nasal mucosa. Like norepinephrine, NPY acts as a vasoconstrictor. An established method of nasal provocation was used to determine the effects of topically applied NPY on nasal resistance to airflow measured by anterior rhinomanometry, the protein content of nasal secretions, and the protein content of bradykinin-induced secretions. NPY (2.3 nmol) reduced the resistance to inspiratory airflow by 57 +/- 18% (P < 0.001) in 10 normal subjects and by 50 +/- 17% (P < 0.05) in 12 subjects with perennial rhinitis. In nasal provocations, NPY in doses of 0.1-10 nmol had no effect on vascular (albumin), glandular (lysozyme, glycoconjugate), or total proteins present in lavaged nasal secretions. Because the vasoconstrictor properties of NPY may only be apparent in the presence of increased vascular permeability and albumin exudation, bradykinin (BK) nasal provocation was performed. BK (500 nmol) significantly increase total protein (10- to 20-fold), albumin (10- to 30-fold), and glycoconjugate (2- to 5-fold) in lavage fluid. NPY (2.3 nmol) reduced BK-induced total protein by 59 +/- 15% (P < 0.05) and albumin by 63 +/- 17% (P < 0.02) but had no significant effect on glandular secretion. Therefore exogenous administration of NPY to the human nasal mucosa reduced nasal airflow resistance and albumin exudation without affecting submucosal gland secretion. NPY agonists may be useful for the treatment of mucosal diseases characterized by vasodilation, vascular permeability, and plasma exudation.

Nasal glandular secretory response to cholinergic stimulation in humans and guinea pigs.

A guinea pig model of nasal secretory responses was developed to assess the contributions of vascular permeability and glandular secretion responsible for the production of cholinergically stimulated nasal secretions. The nasal secretory responses to provocation with saline, methacholine, and atropine on the ipsilateral (challenged) side and contralateral (reflex) side were analyzed by measurement of total protein (Lowry method), guinea pig albumin (enzyme-linked immunosorbent assay), 125I-labeled bovine serum albumin after intravenous injection, and alkaline phosphatase enzyme activity in nasal fluid. Alkaline phosphatase was found to be localized to submucosal glands by zymography. Topical methacholine challenge increased the secretion of total protein, alkaline phosphatase activity, and albumin on the ipsilateral challenged side, whereas the percentage of total protein represented by albumin was not increased. This response was totally prevented by atropine pretreatment. Serial provocation with methacholine resulted in progressively reduced amounts of both the total protein and alkaline phosphatase in secretions. The observation that repeated challenges produced progressively smaller responses was also examined employing human nasal provocation. Repeating methacholine (25 mg) challenges four times at 10-min intervals in six human volunteers revealed that the initial challenge produced the largest response as reflected in total protein, albumin, lysozyme, lactoferrin, immunoglobulin (Ig) G, IgA, and secretory IgA secretion. When the constituents in secretions were analyzed in relationship to the total protein, the two vascular proteins, IgG and albumin, demonstrated the greatest decrements with repeated methacholine challenges. The glandular proteins, lactoferrin, lysozyme, and secretory IgA, either remained constant or increased in their relative proportion to total protein. Thus, cholinergic stimulation causes glandular secretion from both the guinea pig and human nasal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

M1 and M3 muscarinic antagonists inhibit human nasal glandular secretion in vitro.

Mucus glycoproteins (MGP) are high-molecular-weight glycoconjugates that are released from submucosal glands and epithelial goblet cells in the respiratory tract. Muscarinic receptors have an important role in the regulation of human nasal glandular secretion and mucus production, but it is not known which of the five muscarinic receptor subtypes are involved. The effect of nonselective and M1-, M2-, and M3-selective muscarinic antagonists on methacholine (MCh)-induced MGP secretion from human nasal mucosal explants was tested in vitro. MGP was assayed by enzyme-linked immunosorbent assay using a specific anti-MGP monoclonal antibody (7F10). MCh (100 microM) induced MGP secretion up to 127% compared with controls. MCh-induced MGP release was significantly inhibited by atropine (100 microM), the M, receptor antagonist pirenzepine (10-100 microM), and the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; 1-100 microM). 4-DAMP significantly inhibited MCh-induced MGP release at a lower concentration (1 microM) than pirenzepine (10 microM). The M2 receptor antagonists AF-DX 116 and gallamine (both at 100 microM) had no effect. No antagonist alone had a significant effect on MGP release. These results indicate that the M1 and M3 muscarinic receptor subtypes regulate MGP secretion from human nasal mucosa and suggest that the M3 receptor has the predominant effect.

Identification of neutral endopeptidase mRNA in human nasal mucosa.

Neutral endopeptidase (NEP) may regulate peptide-induced inflammation in the upper respiratory tract. NEP mRNA was detected by Northern blotting in poly(A)+ mRNA prepared from human turbinates. NEP mRNA bands were detected at 3.9 and 1.8 kb. In situ hybridization identified NEP mRNA in epithelial cells, serous cells of submucosal glands, and vessel walls. The vacuoles of goblet and mucous cells were not stained, but it is likely that the cytoplasm of these cells contained some NEP mRNA. Radioactive in situ hybridization with 35S-UTP appeared to be more sensitive than nonradioactive in situ hybridization with biotin-UTP and immunogold detection. The NEP mRNA-containing cells identified by in situ hybridization were the same as those identified by immunohistochemistry to contain immunoreactive NEP. These NEP-containing cells have been previously shown to possess peptide receptors. This is consistent with the hypothesis that NEP on cells bearing peptide receptors may regulate neuropeptide-induced inflammation in human nasal mucosa.

Gastrin releasing peptide (GRP) binding sites in human bronchi.

The autoradiographic binding site of gastrin releasing peptide (GRP), the 27 amino acid mammalian form of bombesin, were examined in human bronchial mucosa. 125I-GRP bound specifically to submucosal glands and the epithelium. There was limited binding to vessels and bronchial smooth muscle. These observations suggest that GRP or GRP immunoreactive peptides which are present in nerve fibres and pulmonary neuroendocrine cells, may act upon glandular GRP receptors to induce mucus secretion, but that GRP would probably have little effect on vascular permeability or tracheobronchial smooth muscle tone.

The effects of neuropeptides on mucous glycoprotein secretion from human nasal mucosa in vitro.

The role of neuropeptides in the regulation of macromolecule secretion from human nasal mucosa is incompletely understood. Previous in vitro explant culture studies have demonstrated the effects of neuropeptides on lactoferrin release from serous cells and 3H-glucosamine labeled respiratory glycoconjugate secretion from mucus-containing cells. The generation of a new monoclonal antibody, 7F10, has led to the development of an ELISA for high molecular weight respiratory mucous glycoproteins (MGP). This ELISA was used to measure the ability of sensory, parasympathetic and sympathetic neuropeptides to stimulate MGP release from human nasal mucosal fragments in short term explant culture in vitro. Significant MGP release was stimulated by the sensory neuropeptides gastrin releasing peptide (10 microM GRP: 10.6% +/- 2.4% increase, n = 8, P less than 0.01 vs. control), substance P (1 microM SP: 12.5% +/- 5.4%, n = 11, P less than 0.05), neurokinin A (1 microM NKA: 17.8 +/- 4.3%, n = 6, P less than 0.01), while calcitonin gene related peptide (CGRP) was without effect. Vasoactive intestinal peptide (VIP), a neurotransmitter from parasympathetic nerves, induced significant dose dependent MGP secretion, but had no additive or inhibitory interaction with methacholine-induced secretion. Neuropeptide Y (NPY), present in sympathetic nerves, had no effect on MGP secretion. These observations correlate with the effects of neuropeptides on serous cell lactoferrin secretion, and the presence of specific GRP, SP, and VIP binding sites on human nasal submucosal glands that have been detected by autoradiography. GRP and tachykinins (SP and NKA) from sensory nerves, and VIP released during parasympathetic reflexes may significantly stimulate mucous and serous cell secretion from human nasal mucosa in vivo.

Anaphylaxis.

The syndrome of anaphylaxis is a life-threatening event in which the potential for patient morbidity and mortality is high. An understanding of the pathophysiology of anaphylaxis, the most serious of the allergic disorders, is paramount for its diagnosis. In addition to these elements, this article discusses newly recognized causes of anaphylaxis and reviews its treatment.

Management of the airway in patients with angioedema.

Angiodema can be frequently encountered in clinical practice, and usually represents transient areas of tissue edema and erythema. In general, lesions involve the deep dermis as well as subcutaneous or submucosal sites and can affect multiple organ systems, including the respiratory and gastrointestinal tracts. Although the underlying cause for the angioedema is frequently not known, it can result from atopy, specific antigen sensitivities, physical stimuli, as well as disorders that affect the complement cascade. These latter entities may be congenital or acquired. Pathogenesis for angioedema is generally thought to be activation of mast cells or basophils, with subsequent release of histamine and other mediator products which can induce inflammatory changes. In most patients with physical and allergic causes of angioedema, swelling can usually be treated with epinephrine, antihistamines and/or steroids. Management of the airway in such patients is usually symptomatic, although certain patients require hospitalization for supervised care. On the other hand, patients with hereditary angioedema do not often respond well to these agents. In such patients, we currently add infusions of epsilonaminocaproic acid as well as nembulized racemic epinephrine to our therapeutic regimen, but even this may not be satisfactory. At the National Institute of Allergy and Infectious Disease, endotracheal intubation is usually preferred to tracheostomy for securing a temporary airway, though certain patients may require placement of tracheostomies for better control of the airway. Patients with frequent recurrences of airway obstruction are rarely seen--even among those patients with known hereditary angioedema. However, such patients may require tracheal fenestrations to secure long-term protection of the airway. The Institute's experiences in the management of patients with angioedema are reviewed, and therapies employed are described.

Sinusitis: bench to bedside. Current findings, future directions.

Sinusitis, an inflammatory disease of the sinus, is one of the most commonly reported diseases in the United States, affecting an estimated 14% of the population. The prevalence of sinusitis is rising. Between 1990 and 1992, persons with sinusitis reported approximately 73 million restricted activity days--an increase from the 50 million restricted activity days reported between 1986 and 1988. Because critical questions remain unanswered about its cause, pathophysiology, and optimal treatment, sinusitis continues to generate significant health care costs and affects the quality of life of a large segment of the U.S. population. To identify critical directions for research on sinus disease, the American Academy of Allergy, Asthma and Immunology and the American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc., convened a meeting in January 1996 in collaboration with the National Institutes of Allergy and Infectious Disease. This document summarizes the proceedings of that meeting and presents what is intended to be the background for future investigation of the many unanswered questions related to sinusitis.

Effects of substance P and calcitonin gene related peptide (CGRP) on guinea pig nasal mucosal secretion in vivo.

Trigeminal sensory nerves contain and release the neurotransmitters substance P (SP) and calcitonin gene related peptide (CGRP) in nasal mucosa. The effects of SP and CGRP on nasal secretion were tested in an in vivo model of guinea pig nasal mucosal secretion by topically applying the peptides directly to turbinates, and then lavaging the nostrils 10 min later. Concentrations of total protein, albumin, and 125I-bovine serum albumin (25I-BSA, injected intravenously at time 0 of the studies) were measured in lavage fluid. SP (beginning at 10(-8) M) and CGRP (beginning at 10(-6) M) stimulated the secretion of 125I-BSA indicating stimulation of plasma protein exudation. SP and CGRP increased total protein concentration at 10(-6) M indicating stimulation of glandular secretion. Topically applied thiorphan (1 microgram), an inhibitor of neutral endopeptidase, did not potentiate the maximal response to SP. However, thiorphan significantly prolonged the duration of 125I-BSA, total protein, and albumin secretion in response to SP indicating that the vascular and glandular responses were enhanced. This implies the presence of neutral endopeptidase, and demonstrates a regulatory role for this enzyme in vivo. These findings are consistent with the concept that SP and CGRP released by nociceptive sensory nerve axon responses in guinea pig nasal mucosa lead to plasma extravasation, albumin exudation, and glandular secretion, and that these mechanisms contribute to nasal responses to injury in this species.

Immunological localization of neuropeptide-degrading enzymes in the nasal mucosa.

Neutral endopeptidase (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and carboxypeptidase N (CPN, EC 3.4.17.3) are potentially important enzymes which regulate the degradation of neuropeptides, such as bradykinin (BK) and substance P (SP), in the respiratory mucosa. Some neuropeptides are also degraded by these enzymes in vitro and in vivo. We investigated the localization of these enzymes in the human nasal mucosa by an indirect immunohistochemical technique (immunogold silver staining). NEP-immunoreactive areas were present in the epithelium, the serous cells of the submucosal glands, and the endothelial cells of small vessels. The epithelium and the serous cells were the predominant areas of NEP immunoreactivity in the nasal mucosa. ACE-immunoreactive areas were seen in the outer layer of the epithelium, the endothelial cells of vessels, and widely distributed in the superficial lamina propria. The endothelial cells of the vessels showed maximum positive intensity to ACE. CPN-immunoreactive areas were observed in the epithelium, the endothelium of vessels and the superficial lamina propria, except for the gland cells. The superficial lamina propria exhibited maximum immunoreactivity for CPN. We observed that the enzymes were widely distributed in the nasal mucosa. The epithelium, including the epithelial cells and glycocalyx, contains all three enzymes. These enzymes play an important role in the mucosal immunity of the respiratory mucosa by degrading active neuropeptides. These results show that NEP secretion is regulated by a glandular, cholinergic control. On the other hand, ACE and CPN secretion are regulated by vascular permeability.

Pattern of nasal secretions during experimental influenza virus infection.

To define the pattern of secretion production during influenza virus infection, 28 adult subjects were inoculated with influenza-A virus (H1N1) and cloistered for a period of 8 days. On each day, symptoms associated with virus infection were scored, nasal secretions were collected and nasal lavages were performed. Recovered lavage fluids were submitted for virus culture and assayed for proteins, histamine, and bradykinin. Twenty-one subjects were infected with influenza-A virus and had significant increases in daily secretion weights and symptom scores extending from day 2 to 7, post-inoculation. Plasma-derived proteins in the nasal lavage fluids showed an early increase to peak at day 4 and then decreased. Glandular proteins showed a later increase to peak at day 5. Bradykinin but not histamine was significantly elevated and tracked the changes in the glandular proteins. In contrast, a shallow increase in symptoms confined to day 2 post-inoculation, but no increase in daily secretion weights was documented in the seven uninfected subjects. There, an increase in plasma proteins was observed on days 1 and 2, but no change in glandular proteins was obvious. These results support a biphasic secretory response during influenza-virus infection with transudation dominating the early period and glandular secretions contributing later.