Differential role for T cells in the development of fibrotic lesions associated with reovirus 1/L-induced bronchiolitis obliterans organizing pneumonia versus Acute Respiratory Distress Syndrome

Bronchiolitis obliterans organizing pneumonia (BOOP) and Acute Respiratory Distress Syndrome (ARDS) are two pulmonary diseases with fibrotic components. BOOP is characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intra-alveolar fibrosis. ARDS is a biphasic disease that includes an acute phase, consisting of severe leukocyte infiltration, edema, hemorrhage, and the formation of hyaline membranes, and a chronic phase, which is characterized by persistent intra-alveolar and interstitial fibrosis. CBA/J mice infected with 1 x 10(6) plaque-forming units (pfu) reovirus 1/L develop follicular bronchiolitis and intra-alveolar fibrosis similar to BOOP. In contrast, CBA/J mice infected with 1 x 10(7) pfu reovirus 1/L develop histologic characteristics of ARDS including diffuse alveolar damage, hyaline membranes, and intra-alveolar fibrosis. In this report, we demonstrate a differential role for T lymphocytes in the development of fibrosis associated with BOOP versus ARDS. Neonatally thymectomized CBA/J mice infected with 1 x 10(7) pfu (ARDS) reovirus 1/L still develop the hallmark characteristics of ARDS, including a severe viral pneumonia with cellular infiltrates comprised mainly of macrophages and neutrophils, hyaline membrane formation, and hemorrhage during the acute phase of the disease and persistent intra-alveolar fibrosis during the chronic phase of the disease. In contrast, neonatally thymectomized CBA/J mice infected with 1 x 10(6) pfu (BOOP) reovirus 1/L do not develop intra-alveolar fibrosis associated with BOOP. Therefore, while T cells are necessary for the development of intraluminal fibrosis associated with BOOP, they are not necessary for the development of intraluminal fibrosis associated with ARDS. Furthermore, we suggest that interferon-gamma plays a key role in the fibrotic process and that elevated levels of interferon-gamma are associated with a continuum from least to more severe fibrosis.     

Evolution of three patterns of intra-alveolar fibrosis produced by bleomycin in rats

In pulmonary fibrosis, it is known that fibrotic changes develop in the intra-alveolar spaces and that intra-alveolar fibrosis can be classified into three patterns, namely intraalveolar buds, mural incorporation and obliterative changes. In order to clarify the evolution of intra-alveolar fibrosis, immunohistochemical studies of extracellular matrix proteins and electron microscopic observations were made of the lungs of rats given a single intretracheal instillation of bleomycin. All three patterns of fibrosis developed in this model. Intra-alveolar buds changed into globular lesions with dense collagen deposition, the surface of which was covered by alveolar epithelium. Electron microscopy revealed that the buds often contained spiraling collagen fibrils and numerous microfibrils, but not mature elastic fibres, beneath the regenerating epithelial lining cells; the epithelial basement membranes were discontinuous. In contrast, mural incorporation and obliterative changes ware associated with alveolar structural remodeling. Electron microscopically, these lesions had bundles of normal collagen fibrils, small elastic fibers, and continuous epithelial basement membranes. These results indicate that: (i) intra-alveolar buds, that become intra-alveolar collagen globules, with an unusual extracellular matrix, do not contribute to alveolar structural remodelling; and (ii) areas of mural incorporation and obliterative changes have the usual type of extracellular matrix and are essential for alveolar structural remodeling.     

Respiratory reovirus 1/L induction of intraluminal fibrosis. A model for the study of bronchiolitis obliterans organizing pneumonia.

Bronchiolitis obliterans organizing pneumonia (BOOP) is a term that was first applied in 1985 to describe a long-observed but unclassified pattern of acute lung injury. BOOP lesions are characterized by fibrous extensions into the alveolar spaces in association with a peribronchiolar organizing pneumonia. Since 1985, an increasing number of reports of BOOP have appeared in the clinical literature, and it is now accepted that BOOP is a significant pulmonary syndrome. Although BOOP can be associated with a number of documented pulmonary insults, many cases are not associated with known causes and are thus classified as idiopathic. The lack of an appropriate small animal model that closely mimics the generation of BOOP lesions has been an impediment to basic studies of the pathogenic mechanisms responsible for the generation of BOOP in humans. In this report, we describe an animal model for BOOP in which CBA/J mice infected with reovirus serotype 1/strain Lang develop BOOP lesions. These lesions closely resemble those seen in humans and occur in a well defined temporal sequence that proceeds from initial peribronchiolar inflammatory lesions to characteristic, fibrotic cellular BOOP lesions over a 3-week time course.     

Respiratory reovirus 1/L induction of intraluminal fibrosis, a model of bronchiolitis obliterans organizing pneumonia, is dependent on T lymphocytes

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinical syndrome characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intraalveolar fibrosis. We have developed an animal model of BOOP where CBA/J mice infected with 1 x 10(6) plaque-forming units (PFU) reovirus 1/L develop follicular bronchiolitis and intraalveolar fibrosis similar to human BOOP. In this report, we demonstrate a role for T cells in the development of intraluminal fibrosis associated with BOOP. Corticosteroid treatment of reovirus 1/L-infected mice both inhibited the development of fibrotic lesions when administered early in the time-course and promoted the resolution of fibrotic lesions when corticosteroid administration was delayed. Further, the depletion of either CD4(+) or CD8(+) T cells before reovirus 1/L infection also inhibited fibrotic lesion development. Both corticosteroid treatment and depletion of CD4(+) or CD8(+) T cells also resulted in decreased expression of the proinflammatory and profibrotic cytokines, interferon (IFN)-gamma and monocyte chemoattractant protein-1 (MCP-1). Further, treatment of mice with a neutralizing monoclonal antibody to IFN-gamma also significantly inhibited the development of fibrosis. Taken together, these results suggest a significant role for T cells in the development of reovirus 1/L-induced BOOP fibrotic lesions in CBA/J mice and suggests that T(H)1-derived cytokines, especially IFN-gamma, may play a key role in fibrotic lesion development.     

Presence of platelet-derived growth factor in normal and fibrotic lung is specifically associated with interstitial macrophages, while both interstitial macrophages and alveolar epithelial cells express the c-sis proto-oncogene

Normal lung structure is maintained by the presence of mesenchymal cells and their extracellular matrix products. The slow normal turnover of these cells is disrupted in fibrotic disorders, resulting in the in situ accumulation of mesenchymal cells and their extracellular matrix leading to a progressive alveolar wall thickening. Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disorder of the lung characterized by a diffuse interstitial and intra-alveolar inflammation dominated by macrophages and polymorphonuclear neutrophils. Evaluation of alveolar macrophages (AM) obtained by bronchoalveolar lavage has previously shown that AM from normal individuals spontaneously release small amounts of platelet-derived growth factor (PDGF), a chemotactic and growth factor for mesenchymal cells, whereas AM from IPF patients spontaneously release increased amounts of biologically active PDGF, suggesting its involvement in mesenchymal cell accumulation. However, other cells such as endothelial cells and vascular smooth muscle cells can also release PDGF in vitro. In order to specify PDGF location in lung parenchyma, open lung biopsies from normal individuals and IPF patients were examined by immunohistochemistry using an anti-PDGF antibody and by in situ hybridization using PDGF A-chain and B-chain gene probes. In normal as well as in fibrotic lung, PDGF was only present in relation with interstitial macrophages but not with any other inflammatory cells or mesenchymal cells. Furthermore, the percentage of PDGF-positive macrophages in IPF was 3-fold increased in comparison to normal lung. In addition, the percentage of PDGF-positive macrophages was the same in fibrotic and nonfibrotic areas of IPF lungs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased expression of epimorphin in bleomycin-induced pulmonary fibrosis in mice

Epimorphin was originally identified as a mesenchymal, cell surface-associated protein that modulates epithelial morphogenesis in embryonic organs, whereas pulmonary fibrosis is a process of wound healing, which in part mimics the process of fetal lung development. We investigated the temporal and spatial changes in the distribution of epimorphin protein and expression of its messenger RNA (mRNA) in bleomycin-induced pulmonary fibrosis in mice. Immunohistochemical analysis showed that low levels of epimorphin were present in the bronchiolar, alveolar, and vascular walls of normal adult lungs. However, from Day 7 until Day 28 after bleomycin treatment, increasing levels of epimorphin immunoreactivity were detected in the mesenchymal cells and in the extracellular matrix within intra-alveolar fibrotic lesions. Moreover, Northern blots showed corresponding increases in epimorphin mRNA expression. Re-epithelialization of epimorphin-rich intra-alveolar fibrosis was complete by Day 28 after bleomycin, and by Day 56, epimorphin immunoreactivity had declined. In situ hybridization and confocal microscopic studies confirmed expression of epimorphin mRNA by mesenchymal cells situated within early fibrotic lesions, whereas immunoelectron microscopy localized the epimorphin to the endoplasmic reticulum of the mesenchymal cells and to the basement membrane and collagen fibrils in the area. These results suggest that epimorphin may contribute to the remodeling of pulmonary fibrosis via epithelial-mesenchymal interactions.     

Cell-matrix patterns in the cutaneous lesion of chromomycosis.

Chromomycosis is a chronic fungal infection characterized by dermal fibrosis with persisting fungi in situ, generally leading to a verrucous skin lesion. The absence of good clinical results under specific treatment suggests irreversibility of the fibrotic lesion. Frozen and paraffin-embedded skin biopsies of eleven patients with chromomycosis due to Phialophora pedrosoi were studied by immunohistochemistry and electron microscopy. Distinct cell-matrix patterns were found in different tissue localizations: neutrophilic abscesses with oedema and necrotic keratinocytes in the epidermis; dense connective matrix around inflammatory infiltrates, mainly composed of macrophages and giant cells, and organized granuloma in the dermis. Active fibroblasts and mast cells were constantly observed. The inability of fibrotic tissue to be remodelled seems correlated to the nature and the organization of the matrix components but, the factors triggering the initial fibrogenic events remain to be characterized.     

Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland.

Development of the ductal network in the mammary gland is dependent in part on the presence of macrophages. Here we utilize multi-photon microscopy and second harmonic generation to describe terminal end bud 3-dimensional structure and the organization of the surrounding collagen matrix. We have applied this approach to analyze the effect of macrophage deficiency on terminal end bud structure and collagen organization, using mice homozygous for a null mutation in the colony stimulating factor-1 gene (Csf1op/Csf1op). Primary terminal end buds have an oblong shape, with long collagen I fibers close to the neck of the terminal end bud and radiating upwards in the direction of growth. Around the terminal end buds, the amount of total collagen I detected by antibody staining was not affected by macrophage deficiency. However the amount of collagen I organized into long fibers, detected by second harmonic generation signal, was reduced in Csf1op/Csf1op mice. Macrophage deficiency also caused terminal end buds to be rounder and shorter. These studies reveal a role for macrophages in collagen fibrillogenesis and in organization of the structure of terminal end buds.     

Postnatal development of the vallate papilla and taste buds in rats

The postnatal maturation of the vallate papilla and its taste buds was quantitatively investigated in rats by ligh microscopy. Specifically, we measured postnatal increases in the size of mature vallate taste buds and the vallate papilla, increases in the thickness of the gustatory epidermis, and increases in the number of mature taste buds and taste cells per bud. Mature taste buds, defined as those having a taste pore, are rare at birth but proliferate rapidly during the first postnatal month until an average of 610 mature taste buds has accumulated by 90 days. Throughout this postnatal period, mature taste buds adjust to the developmental thickening of the epidermis by continuously increasing in length. Mature taste buds also increase in width, in part due to a threefold increase from 10 and 45 days in the number of taste cells per bud. From 10 to 21 days there is an average daily net increase of three cells per mature taste bud. The maturational increase in taste buds and cells may contribute to the functional changes in taste nerve responses known to occur over the course of several generations of taste receptor cells. The dimensions of the vallate papilla and the surface area of the gustatory epithelium increase logarithmically with age. Although mature taste buds continue to increase in number until 90 days, both taste bud density (178/mm2) and the number of cells per mature taste bud (70-75 cells) reach ceilings by 45 days. Thus, density-dependent factors appear to control vallate taste bud maturation. The immaturity of lingual taste buds in newborn rats supports the view that odor, rather than taste, is the chemosensory signal that guides suckling in altricial rodents.     

Cell contact-dependent mechanisms specify taste bud pattern during a critical period early in embryonic development.

After gastrulation, the pharyngeal endoderm is specified to give rise to taste receptor organs without further signaling from other embryonic tissues. We hypothesized that intercellular signaling might be responsible for the specification of taste buds. To test if and when this signaling was occurring, intercellular contacts were transiently disrupted in cultures of pharyngeal endoderm from axolotl embryos, and the number, size, and distribution of taste buds analyzed. Disruption of cell contacts at progressive time points, from neurula to late tail bud stages, revealed a critical period, during mid-tail bud stages, when disruption of cell contacts resulted in a significant increase in taste bud number and size. The spatial distribution of taste buds was also altered; taste buds were more clustered in explants disrupted during the critical period. These effects were not due to general alterations in mitosis and apoptosis. Rather, at least three aspects of taste bud patterning, i.e., number, size, and distribution, are governed by mechanisms dependent on normal cell contacts during a concise time window. Furthermore, our findings are consistent with specification of taste buds by means of lateral inhibitory signaling, which we hypothesize results from cell contact-dependent or short-range diffusible signals.     

Induction of bud formation of embryonic mouse tracheal epithelium by fibroblast growth factor plus transferrin in mesenchyme-free culture.

Embryonic mouse tracheal epithelium, which branches in an epithelial-mesenchymal recombination culture with bronchial mesenchyme, was cultured under mesenchyme-free conditions. When embedded in a basement-membrane-like matrix and cultured in a serum-free medium supplemented with fibroblast growth factor 1 (FGF1), the tracheal epithelium did not branch, whereas the bronchial epithelium underwent branching morphogenesis. When the medium was enriched with transferrin (Tf), bud formation was induced in the tracheal epithelium and some buds branched secondarily. FGF7 and FGF10, in cooperation with Tf, induced tracheal bud formation to the same extent as FGF1, although the optimum concentrations differed. A bromodeoxyuridine-labeling study comparing cultures with and without Tf showed no Tf-specific amplification of cell proliferation. A whole-mount in situ hybridization study of the expression of Bmp4 and Shh genes in explants of mesenchyme-free culture revealed that both genes were ubiquitously expressed and that expression did not correlate with bud formation. This expression pattern was different from the distally localized expression pattern observed in normal lung rudiments and in extratracheal buds induced by the recombined bronchial mesenchyme. These results suggest that both bronchial and tracheal bud formations were initiated without localized exposure of the epithelium to FGFs and were not accompanied by localized expression of Bmp4 and Shh in the epithelium.     

Fine structure of the taste bud in guinea pigs. I. Cell characterization and innervation patterns

Guinea pig taste buds were observed by transmission electron microscopy with special reference to cell types and innervation. The taste bud comprised four distinct cell types: basal, type I, type II, and type III cells. Basal cells, residing at the baso-lateral region of the taste bud without extending to the taste pore, were considered precursors of the other types of cells. The rest were all spindle-shaped cells reaching apically to the taste pit. Type I cells were characterized by the darkest appearance of the cytoplasm, apically possessing large, electron-dense granules and basally enveloping intragemmal nerves. This cell type, intervening between the other types of cells, was postulated to be sustentacular in nature. Type II cells, the largest and lightest cells in the taste bud, possessed a conspicuous stack of smooth endoplasmic reticulum above the nucleus. Due to their intimate and specialized relationships with nerves, the type II cells were presumed to receive an efferent innervation. Type III cells made synaptic contacts with nerves and contained dense-cored vesicles, which accumulated in the synaptic areas. This finding strongly suggests a gustatory function for the cells. The occurrence of such numerous peptidergic-type granules gathering to gustatory synapses as demonstrated in this report has not been recorded in previous papers on mammalian taste buds. The nerve terminals on the type III cell also contained synaptic vesicles, thus suggesting a reciprocal synapse here. The taste bud often included degenerating cells which were demonstrated to be phagocytosed by extrinsic cells identified as macrophages.     

TUNEL staining and electron microscopy studies of apoptotic changes in the guinea pig vallate taste cells after unilateral glossopharyngeal denervation

On the basis of our previous report that unilateral glossopharyngeal neurectomy in the guinea pig resulted in degeneration and disappearance of taste buds in ipsilateral vallate papillae (Huang and Lu 1996), it is reasonable to speculate that gustatory denervation may enhance apoptosis of taste bud cells, with taste buds decreasing in number and ultimately disappearing after neurectomy. We were therefore determined to investigate apoptosis of taste bud cells in guinea pig vallate papillae after unilateral glossopharyngeal neurectomy using both terminal deoxynuleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) at the light microscopic level and by conventional electron microscopy. A total of 34 adult guinea pigs were unilaterally glossopharyngeal-neurectomized and sacrificed at 3, 6, 12 h and 1, 3 and 7 days after surgery. The results revealed that only a very few TUNEL-positive nuclei indicating apoptosis were present in normal taste buds, but in surgically denervated papillae, they increased in number from 6 h–12 h after surgery, reached at peak on day 1 and then gradually decreased. In apoptotic cells from normal taste buds, electron microscopy revealed condensation of the chromatin against the nuclear envelope, changes in the nuclear envelope, and fragmentation of the nucleus, but the integrity of the plasma membrane and organelles was maintained. Neurectomized taste cells were also characterized by condensed and fragmentary nuclei, compactness of the cytoplasmic organelles, and the appearance of pedunculated protuberances on the cell surface. From these observations, we conclude that: (1) glossopharyngeal neurectomy enhanced apoptosis of vallate taste bud cells in guinea pig; (2) appropriate gustatory nerve innervation is an essential component for the maintenance of the taste bud, and may play a role in apoptosis of taste cells. Accepted: 15 August 2001     

Organization of geniculate and trigeminal ganglion cells innervating single fungiform taste papillae: a study with tetramethylrhodamine dextran amine labeling.

Single gustatory nerve fibers branch and innervate several taste buds. In turn, individual taste buds may receive innervation from numerous gustatory nerve fibers. To evaluate the pattern of sensory innervation of fungiform papilla-bearing taste buds, we used iontophoretic fluorescent injection to retrogradely label the fibers that innervate single taste papillae in the hamster. For each animal, a single taste papilla was injected through the gemmal pore with 3.3% tetramethylrhodamine dextran amine. Fungiform papillae either at the tongue tip (0.5-1.5 mm from the tip) or more posteriorly (1.5-3.0 mm from the tip) were injected. After one to seven days survival, the geniculate and trigeminal ganglia and the tongue were sectioned and examined for labeled cells and fibers, respectively. Analysis of the number and topographic distribution of geniculate cells innervating single taste papillae, shows that: (i) 15 +/- 4 (S.D.) ganglion cells converge to innervate a single fungiform taste bud; (ii) more ganglion cells innervate anterior- (range: 13-35 cells) than posterior-lying buds (range: five to 12 cells), which, in part, may be related to bud volume (microm3); and (iii) ganglion somata innervating a single taste bud are scattered widely within the geniculate ganglion. Analysis of labeled fibers in the tongue demonstrated that two to eight taste buds located within 2 mm of the injected taste bud share collateral innervation with the injected taste bud. Since all buds with labeled fibers were located in close proximity (within a 2-mm radius), widely dispersed geniculate ganglion cells converge to innervate closely spaced fungiform taste buds. Trigeminal ganglion (mandibular division) cells were also labeled in every case and, as with the geniculate ganglion, a dispersed cell body location and collateralization pattern among papillae were observed. This study shows that iontophoresis of tetramethylrhodamine dextran amine, selectively applied to individual peripheral receptor end-organs, effectively locates sensory ganglion cells in two different ganglia that project to these sites. Moreover, the marker demonstrates collateral branches of sensory afferents associated with the labeled fibers and the nearby receptor areas innervated by these collaterals. The labeling of single or clusters of receptor cells, as well as identified sensory afferents, affords future possibilities for combining this technique with immunocytochemistry to establish the relationships of innervation patterns with neurotransmitters and neurotropic substances within identified cells.     

Taste bud development in chickens (Gallus gallus domesticus)

Oral epithelium in the anterior mandibular glands region was examined in embryonic, hatchling, and mature chickens to establish the timing of morphologic events during taste bud ontogeny. Hematoxylin-and-eosin-stained sections (10 microns) from 27 Anak (broiler breed) chickens were examined serially, and buds were quantified at 16-20 days of incubation (E) and, posthatch days 1 and 50-60. Taste buds were first recognized at the beginning of E17 as small clusters of cells in the basal epithelium. Only spherical-shaped buds were observed on E17 and E18, and these spherical clusters never penetrated to the surface of the stratified epithelial layer. E19 marked a transitional stage when mature bud features began to emerge: the buds assumed a more elongate shape, several kinds of cells comprising the bud were distinguishable and the first taste pores were observed. During the ensuing embryonic days, buds continued to elongate commensurate with the deepening oral epithelium and by hatching virtually all buds opened to the oral cavity. No marked morphological changes in taste bud structure were observed on the day of hatching and at 50-60 days posthatching. Taste bud numbers increased dramatically during E17 and E18, peaked on E19, and remained relatively constant thereafter. It is concluded that the morphological sequence of taste bud development in chickens is similar to that in mammals. The timing of bud ontogeny, though initiated only during the third trimester in ovo, essentially is completed by hatching, thus providing the precocial hatchling with the sensory apparatus essential for gustatory experience.     

Development and maturation of taste buds of the palatal epithelium of the rat: histological and immunohistochemical study.

Palatal taste buds are intriguing partners in the mediation of taste behavior and their spatial distribution is functionally important for suckling behavior, especially in the neonatal life. Their prenatal development has not been previously elucidated in the rat, and the onset of their maturation remains rather controversial. We delineated the development and frequency distribution of the taste buds as well as the immunohistochemical expression of alpha-gustducin, a G protein closely related to the transduction of taste stimuli, in the nasoincisor papilla (NIP) and soft palate (SP) from the embryonic day 17 (E17) till the postnatal day 70 (PN70). The main findings in the present study were the development of a substantial number of taste pores in the SP of fetal rats (60.3 +/- 1.7 out of 122.8 +/- 5.5; mean +/- SD/animal at E19) and NIP of neonatal rats (9.8 +/- 1.0 out of 44.8 +/- 2.2 at PN4). alpha-gustducin-like immunoreactivity (-LI) was not expressed in the pored taste buds of either prenatal or newborn rats. The earliest expression of alpha-gustducin-LI was demonstrated at PN1 in the SP (1.5 +/- 0.5 cells/taste bud; mean +/- SD) and at PN4 in the NIP (1.4 +/- 0.5). By age the total counts of pored taste buds continuously increased and their morphological features became quite discernible. They became pear in shape, characterized by distinct pores, long subporal space, and longitudinally oriented cells. Around the second week, a remarkable transient decrease in the total number of taste buds was recorded in the oral epithelium of NIP and SP, which might be correlated with the changes of ingestive behaviors. The total counts of cells showing alpha-gustducin-LI per taste bud gradually increased till the end of our investigation (14.1 +/- 2.7 in NIP and 12.4 +/- 2.5 in SP at PN70). We conclude that substantial development of taste buds began prenatally in the SP, whereas most developed entirely postnatal in the NIP. The present study provides evidence that the existence of a taste pore which is considered an important criterion for the morphological maturation of taste buds is not enough for the onset of the taste transduction, which necessitates also mature taste cells. Moreover, the earlier maturation of palatal taste buds compared with the contiguous populations in the oral cavity evokes an evidence of their significant role in the transmission of gustatory information, especially in the early life of rat.     

Variation in human fungiform taste bud densities among regions and subjects

Taste sensitivity is known to vary among regions of the tongue and between subjects. The distribution of taste buds on the human tongue is examined in this report to determine if interregional and intersubject variation of taste bud density might account for some of the variation in human taste sensitivity. The subjects were ten males, aged 22-80 years, who died from acute trauma or an acute cardiovascular episode. Specimens were obtained as anatomical gifts or from autopsy. A sample of tissue about 1 cm2 was taken from the tongue tip and midlateral region; frozen sections were prepared for light microscopy; and serial sections were examined by light microscopy to count the taste buds. The average taste bud (tb) density on the tongue tip was 116 tb/cm2 with a range from 3.6 to 514 among subjects. The number of gustatory papillae on the tip averaged 24.5 papillae/cm2 with a range from 2.4 to 80. Taste bud density in the midregion averaged 25.2 tb/cm2 (range: 0-85.9), and the mean number of gustatory papillae was 8.25/cm2 (range: 0-28). The mean number of taste buds per papilla was 3.8 +/- 2.2 (s.d.) on the tip and 2.6 +/- 1.5 (s.d.) on the midregion. Subjects with the highest taste bud densities on the tip also had the highest densities in the midregion and the highest number of taste buds per papilla. Taste bud density was 4.6 times higher on the tip than the midregion, which probably accounts for some of the regional difference in taste sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchiolitis interstitial pneumonitis: a pathologic study of 31 lung biopsies with features intermediate between bronchiolitis obliterans organizing pneumonia and usual interstitial pneumonitis, with clinical correlation

Bronchiolitis combined with interstitial pneumonitis generally has been equated with bronchiolitis obliterans organizing pneumonia (BOOP). We describe our experience with lung biopsies that had both bronchiolar and interstitial diseases. We studied 31 patients who had respiratory difficulty leading to open lung biopsy, which showed a combination of both prominent bronchiolitis and prominent interstitial pneumonitis. We compared these cases clinically and pathologically with 6 other pulmonary diseases, namely, bronchiolitis obliterans, BOOP, nonspecific interstitial pneumonitis, usual interstitial pneumonitis, airway-centered interstitial fibrosis, and idiopathic bronchiolocentric interstitial pneumonia, and with 10 cases of cystic fibrosis, an unrelated disease with both bronchiolar and interstitial pathology. The commonality of our cases was a combination of bronchiolitis and interstitial inflammation and fibrosis but little or no intra-alveolar organizing pneumonia. Bronchiolitis obliterans with organizing pneumonia involved less area than the interstitial pneumonitis in each case. All 19 patients for whom we had follow-up received corticosteroids for their pulmonary diseases. Seven patients had improvement in symptoms and pulmonary function test results and radiographic findings, 5 patients experienced subjective improvement with unchanged results of pulmonary function tests or chest x-ray, 1 patient's condition was unchanged, 6 patients' disease worsened, and 4 of these 6 died. The natural history of these cases, which we have designated bronchiolitis interstitial pneumonitis, seems more sanguine than usual interstitial pneumonitis and worse than BOOP at least in the short term. On the one hand, response to corticosteroids was not as frequent as generally accepted for BOOP. On the other hand, disease did not progress in most patients on corticosteroids.