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Biomedical subjects

M Friedman

Publications and source records attributed to M Friedman.

At least 73 records · Page 4Linked to original sources
PubMed1999

Lysinoalanine in food and in antimicrobial proteins.

Heat and alkali treatment of food proteins widely used in food processing results in the formation of crosslinked amino acids such as lysinoalanine, ornithinoalanine, lanthionine, and methyl-lanthionine and concurrent racemization of L-amino acid isomers to D-analogues. The mechanism of lysinoalanine formation is a two-step process: first, hydroxide ion-catalyzed elimination of cysteine and serine residues to a dehydroalanine intermediate; second, reaction of the double bond of dehydroalanine with the epsilon-NH2 group of lysine to form a lysinoalanine crosslink. The corresponding elimination-addition reaction of threonine produces methyl-dehydroalanine, which then reacts with the NH2 and SH groups to form methyl-lysinoalanine and methyl-lanthionine, respectively. The crosslinked amino acids lanthionine and methyl-lanthionine are formed by analogous nucleophilic addition reactions of the SH group of cysteine to dehydroalanine and methyl-dehydroalanine, respectively. Processing conditions that favor these transformations include high pH, temperature and exposure time. Factors which minimize lysinoalanine formation include the presence of SH-containing amino acids such as cysteine, N-acetyl-cysteine, and glutathione, dephosphorylation of O-phosphoryl esters, and acylation of epsilon-NH2 groups of lysine side chains. The presence of lysinoalanine residues along a protein chain decreases digestibility and nutritional quality in rodents but enhances nutritional quality in ruminants. Protein-bound and free lysinoalanines are reported to induce enlargement of nuclei of rat kidney cells. All of the mentioned dehydro and crosslinked amino acids also occur naturally in certain peptide and protein antibiotics. These include duramycin, cinnamycin, epidermin, subtilin and the widely used food preservative nisin. Mechanistic rationalizations are offered for the observed antimicrobial activities of these compounds in relation to their structures. The cited findings and new research to better define the chemistry and dietary and antimicrobial roles of lysinoalanine and related compounds should lead to better and safer foods.

Animals↗
PubMed1999

Postharvest changes in glycoalkaloid content of potatoes.

Potatoes contain antinutritional and potentially toxic compounds including inhibitors of digestive enzymes, hemagglutinins, and glycoalkaloids. Solanum glycoalkaloids are reported to inhibit cholinesterase, disrupt cell membranes, and induce teratogenicity. In this overview, we describe the role of potatoes in the human diet, reported changes in glycoalkaloid content of fresh and processed potatoes during storage, under the influence of light and radiation, following mechanical damage, and as a result of food processing. Also covered are safety aspects and suggested research needs to develop a protocol that can be adopted by the potato producers and processors to minimize post-harvest synthesis of glycoalkaloids in potatoes. Reducing the glycoalkaloid content of potatoes will provide a variety of benefits extending from the farm to processing, shipping, marketing, and consumption of potatoes and potato products. A commercially available ELISA kit is described which permits rapid assay of glycoalkaloid content of parts of the potato plant including leaves, tubers, and peel, as well as processed potato products including french fries, chips, and skins. Understanding the multiple overlapping aspects of glycoalkaloids in the plant and in the diet will permit controlling postharvest glycoalkaloid production for the benefit of the producer and consumer.

Folic Acid↗
PubMed1999

Early detection and treatment of postoperative pharyngocutaneous fistula.

Fever during the early postoperative period traditionally has not been considered an indication of a postoperative wound infection or breakdown. Atelectasis is considered the most likely source for these early fevers. We studied 200 consecutive patients who underwent major head and neck surgery that involved reconstruction with a pharyngeal suture line. Patients were divided into 2 groups: those who had preoperative irradiation and those who did not. All patients had prophylactic antibiotic coverage, and all patients had identical suture material for closure. We showed a high correlation between fever (>101.5 degrees F) that developed in the first 48 hours and eventual fistula formation and wound infection. We also studied length of hospitalization and number of days until decannulation and resumption of oral feedings. Our data indicate that in those patients in whom fistulas developed, early detection led to earlier healing and rehabilitation.

Antibiotic Prophylaxis↗
PubMed1999

The effect of parabens in a mouthwash and incorporated into a sustained release varnish on salivary bacteria.

OBJECTIVES: The purpose of this study was to evaluate the antimicrobial efficacy of parabens, in a mouthwash and in a slow release device, against cariogenic bacteria in the oral cavity. METHODS: Parabens were formulated in a mouthwash or in a topical slow release varnish preparation. In two separate studies, volunteers were asked to use the mouthwash or the slow release varnish applied in a personal night guard device. The levels of mutans streptococci (MS), Lactobacilli (LB) and total cultivated bacteria were measured before and after using the mouthwash or the slow release varnish. RESULTS: The mouthwash containing parabens had a minor and a short-term effect on MS and LB counts in human saliva. The use of slow release varnish containing parabens, applied in a night guard, had a prolonged antibacterial effect on both MS and LB counts. CONCLUSIONS: Parabens in a mouthwash had little effect on oral bacteria counts; however, paraben in the slow release device had a significant and an extended effect in reducing oral bacteria. Although substantial reductions in oral bacterial counts were recorded after the use of parabens in a slow release device, this effect could probably be enhanced by an improved pharmaceutical formulation.

Administration, Topical↗
PubMed1999

Chemistry, biochemistry, nutrition, and microbiology of lysinoalanine, lanthionine, and histidinoalanine in food and other proteins.

Heat and alkali treatments of foods, widely used in food processing, result in the formation of dehydro and cross-linked amino acids such as dehydroalanine, methyldehydroalanine, beta-aminoalanine, lysinoalanine (LAL), ornithinoalanine, histidinoalanine (HAL), phenylethylaminoalanine, lanthionine (LAN), and methyl-lanthionine present in proteins and are frequently accompanied by concurrent racemization of L-amino acid isomers to D-analogues. The mechanism of LAL formation is a two-step process: first, hydroxide ion-catalyzed elimination of H(2)S from cystine and H(2)O, phosphate, and glycosidic moieties from serine residues to yield a dehydroalanine intermediate; second, reaction of the double bond of dehydroalanine with the epsilon-NH(2) group of lysine to form LAL. Analogous elimination-addition reactions are postulated to produce the other unusual amino acids. Processing conditions that favor these transformations include high pH, temperature, and exposure time. Factors that minimize LAL formation include the presence of SH-containing amino acids, sodium sulfite, ammonia, biogenic amines, ascorbic acid, citric acid, malic acid, and glucose; dephosphorylation of O-phosphoryl esters; and acylation of epsilon-NH(2) groups of lysine. The presence of LAL residues along a protein chain decreases digestibility and nutritional quality in rodents and primates but enhances nutritional quality in ruminants. LAL has a strong affinity for copper and other metal ions and is reported to induce enlargement of nuclei of rats and mice but not of primate kidney cells. LAL, LAN, and HAL also occur naturally in certain peptide and protein antibiotics (cinnamycin, duramycin, epidermin, nisin, and subtilin) and in body organs and tissues (aorta, bone, collagen, dentin, and eye cataracts), where their formation may be a function of the aging process. These findings are not only of theoretical interest but also have practical implications for nutrition, food safety, and health. Further research needs are suggested for each of these categories. These overlapping aspects are discussed in terms of general concepts for a better understanding of the impact of LAL and related compounds in the diet. Such an understanding can lead to improvement in food quality and safety, nutrition, microbiology, and human health.

Alanine↗
PubMed1999

Sampling leaves of young potato (Solanum tuberosum) plants for glycoalkaloid analysis.

Earlier attempts to measure potato (Solanum tuberosum) leaf glycoalkaloids indicated variability among similar plants, suggesting that a single small sampling of a young plant might not be a reliable measure of composition. It was also suggested that freeze-dried leaf samples might be less variable than fresh ones. In the present work, variability was minimized by comparing single leaves from the same stem position of each plant. Comparisons involving other leaves indicated that the glycoalkaloid content was not constant with respect to either time or position on the stem. In addition, the possible influence of differences in growing conditions at different times suggests that repeated plantings should include a known variety as a control to which other plants are compared. Variability was reduced by calculating glycoalkaloid concentrations on a dry weight rather than fresh weight basis. The method of drying the samples, however, had no influence on the variability of data. These considerations should be generally applicable to the sampling of replicate leaves of any plant for analysis of any components.

Freeze Drying↗
PubMed1999

Chemistry, nutrition, and microbiology of D-amino acids.

Exposure of food proteins to certain processing conditions induces two major chemical changes: racemization of all L-amino acids to D-isomers and concurrent formation of cross-linked amino acids such as lysinoalanine. Racemization of L-amino acids residues to their D-isomers in food and other proteins is pH-, time-, and temperature-dependent. Although racemization rates of the 18 different L-amino acid residues in a protein vary, the relative rates in different proteins are similar. The diet contains both processing-induced and naturally formed D-amino acids. The latter include those found in microorganisms, plants, and marine invertebrates. Racemization impairs digestibility and nutritional quality. The nutritional utilization of different D-amino acids varies widely in animals and humans. In addition, some D-amino acids may be both beneficial and deleterious. Thus, although D-phenylalanine in an all-amino-acid diet is utilized as a nutritional source of L-phenylalanine, high concentrations of D-tyrosine in such diets inhibit the growth of mice. Both D-serine and lysinoalanine induce histological changes in the rat kidney. The wide variation in the utilization of D-amino acids is illustrated by the fact that whereas D-methionine is largely utilized as a nutritional source of the L-isomer, D-lysine is totally devoid of any nutritional value. Similarly, although L-cysteine has a sparing effect on L-methionine when fed to mice, D-cysteine does not. Because D-amino acids are consumed by animals and humans as part of their normal diets, a need exists to develop a better understanding of their roles in nutrition, food safety, microbiology, physiology, and medicine. To contribute to this effort, this multidiscipline-oriented overview surveys our present knowledge of the chemistry, nutrition, safety, microbiology, and pharmacology of D-amino acids. Also covered are the origin and distribution of D-amino acids in the food chain and in body fluids and tissues and recommendations for future research in each of these areas. Understanding of the integrated, beneficial effects of D-amino acids against cancer, schizophrenia, and infection, and overlapping aspects of the formation, occurrence, and biological functions of D-amino should lead to better foods and improved human health.

Amino Acids↗
PubMed1999

Inheritance of morphological characters and glycoalkaloids in potatoes of somatic hybrids between dihaploid Solanum acauleand tetraploid Solanum tuberosum.

Steroidal glycoalkaloids occur in potatoes and are reported to impart resistance to phytopathogens including bacteria, fungi, and insects. Because glycoalkaloids can be passed to progenies during breeding programs designed to develop improved potatoes, it is of importance to determine the quality of desired characteristics and the composition of glycoalkaloids of new somatic hybrids. The objective of this study was to determine the appearance, size, and shape (morphological characters) as well as the glycoalkaloid content of potato tubers of somatic hybrids between tetraploid Solanum tuberosum cv. Dejima (2n = 4x = 48 chromosomes) and the dihaploid clone ATDH-1 (2n = 2x = 24 chromosomes) induced by anther culture from Solanum acuale-T (acl-T, 2n = 4x = 48 chromosomes). Tuber size and shape in somatic hybrids were in accord with those of cv. Dejima, whereas the tuber skin color resembled that of ATDH-1. Thin-layer chromatography, high-performance liquid chromatography, and gas-liquid chromatography/mass spectrometry studies showed that the two steroidal glycoalkaloids (alpha-chaconine and alpha-solanine) were present in the tubers of S. tuberosum, whereas acl-T and ATDH-1 tubers were found to contain alpha-tomatine and demissine. The concentrations of total glycoalkaloids in both acl-T and ATDH-1 was >100 mg/100 g of fresh weight tuber cortex, much higher than in S. tuberosum. All somatic hybrids, except one clone, contained four glycoalkaloids (alpha-chaconine, alpha-solanine, alpha-tomatine, and demissine) derived from the fusion parents. The lack of alpha-tomatine in the remaining clone may be due to somaclonal variation. The results show that character expression is influenced by ploidy level and that total glycoalkaloid levels in most somatic hybrids were intermediate between those of the fusion parents. The possible significance of these findings for plant breeding and food safety is discussed.

Agriculture↗
PubMed1999

Improved lipid lowering activity of bezafibrate following continuous gastrointestinal administration: pharmacodynamic rationale for sustained release preparation of the drug.

PURPOSE: To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other "gastrointestinal (GI) drugs." Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. METHODS: The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. RESULTS: In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. CONCLUSIONS: The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.

Animals↗
PubMed1999

Fetal epidermal differentiation and barrier development In vivo is accelerated by nuclear hormone receptor activators.

Nuclear receptors which interact with the retinoid X receptor are involved in the regulation of epidermal differentiation and development. We have recently shown that activators of the peroxisome proliferator-activated receptor and of the farnesoid X-activated receptor accelerate epidermal barrier maturation in fetal rat skin in vitro. In this study we asked whether cutaneous development in utero was affected by peroxisome proliferator-activated receptor or farnesoid X-activated receptor activators, or by an activator of another retinoid X receptor partner, liver X receptor. Activators of the peroxisome proliferator-activated receptor (clofibrate or linoleic acid), farnesoid X-activated receptor (farnesol or juvenile hormone III), or liver X receptor (22R-hydroxycholesterol), were injected into the amniotic fluid of fetal rats on gestational day 17. Fetal epidermal barrier function and morphology was assessed on day 19. Whereas vehicle-treated fetal rats displayed no measurable barrier (transepidermal water loss > 10 mg per cm2 per h), a measurable barrier was induced by the intra-amniotic administration of all activators tested (transepidermal water loss range 4.0-8.5 mg per cm2 per h). By light microscopy, control pups lacked a well-defined stratum corneum, whereas a distinct stratum corneum and a thickened stratum granulosum were present in treated pups. By electron microscopy, the extracellular spaces of the stratum corneum in control pups revealed a paucity of mature lamellar unit structures, whereas these structures filled the stratum corneum interstices in treated pups. Additionally, protein and mRNA levels of loricrin and filaggrin, two structural proteins of stratum corneum, were increased in treated epidermis, as were the activities of two lipid catabolic enzymes critical to stratum corneum function, beta-glucocerebrosidase and steroid sulfatase. Finally, peroxisome proliferator-activated receptor-alpha and -delta and liver X receptor-alpha and -beta mRNAs were detected in fetal epidermis by reverse transcriptase-polymerase chain reaction and northern analyses. The presence of these receptors and the ability of their activators to stimulate epidermal barrier and stratum corneum development suggest a physiologic role for peroxisome proliferator-activated receptor and liver X receptor and their endogenous ligands in the regulation of cutaneous development.

Amnion↗
PubMed1999

Quantification of lymph nodes in selective neck dissection.

OBJECTIVES: Provide reference for surgeon and pathologist regarding expected yield from selective neck dissections. Quantify lymph nodes obtained from cadaver dissection based on current nodal classification and compare with clinical series. STUDY DESIGN: 1. Quantification of lymph nodes at levels I-V harvested from human cadavers and correlation with nodal grouping for supraomohyoid (I-III) and lateral (II-IV) neck dissections. 2. Retrospective review of operative specimens from clinical neck dissections for lymph node quantity. METHODS: 1. Twenty radical neck dissection specimens, harvested from 10 fresh human cadavers without evidence of head and neck cancer, were separated by nodal level for gross and microscopic examination by a pathologist. The quantity of nodes obtained per level for each specimen was tabulated. 2. Charts of patients treated with neck dissection for squamous cell carcinoma were reviewed and tabulated for type of dissection and number of lymph nodes reported. RESULTS: In the 20 cadaver neck dissections, the average number of lymph nodes removed for levels I-V was 24, with 13 for levels I-III and 19 for levels II-IV. In the clinical review, 98 total neck dissections were included. In the six supraomohyoid dissections, an average of 20 lymph nodes (range, 14-26) were found, with an average of 30 (range, 15-43) in the 11 lateral compartment specimens. In 81 radical or modified radical dissections, an average of 31 nodes (range, 19-63) was reported. CONCLUSIONS: The number of lymph nodes removed in selective neck dissection should be comparable to that of the corresponding levels in radical neck dissection, provided that strict adherence to surgical boundaries is maintained. Dissection of normal cadavers provides a reference for the surgeon and the pathologist but may under-represent lymph node quantity in the diseased state.

Carcinoma, Squamous Cell↗
PubMed1999

Effects of middle turbinate medialization on olfaction.

OBJECTIVE/HYPOTHESIS: Turbinate medialization techniques have gained popularity in an attempt to prevent turbinate lateralization. Theoretically, adhesions between the septum and middle turbinate will prevent lateralization but may compromise airflow to the olfactory neuroepithelium and affect the sense of smell. No studies have addressed this issue. The objective of this study is to evaluate effects of middle turbinate medialization on olfaction. STUDY DESIGN: A prospective controlled study of olfaction before and after middle turbinate medialization using the University of Pennsylvania Smell Identification Test (UP-SIT) and patient questionnaires. METHODS: Fifty patients underwent endoscopic sinus surgery (ESS) with middle turbinate medialization and preservation. The caudal end of the middle turbinate and the opposing septal mucosa were abraded with a microdebrider for iatrogenic synechia formation in an attempt to avoid lateralization of the middle turbinate. Each of the patients underwent preoperative assessment with a questionnaire and UPSIT. All patients were reevaluated approximately 5 weeks after surgery by endoscopic examination, questionnaire, and the UPSIT. The preoperative and postoperative questionnaire responses were compared for subjective analysis. Objectively, the preoperative and postoperative UPSIT scores were compared using the Student t test. RESULTS: The questionnaires showed that the study population's subjective sense of smell either did not change or improved compared with the preoperative state. Objectively, there was a mean increase of UPSIT scores after surgery. This difference was not statistically significant (P = .4). CONCLUSION: Middle turbinate medialization has no detectable adverse effect on olfaction.

Adult↗
PubMed1999

A safe, alternative technique for inferior turbinate reduction.

OBJECTIVE: Submucous resection of the inferior turbinates is a conventional technique for reducing their size to achieve patent nasal airways in situations where an enlarged turbinate contributes to airway obstruction. Many techniques and complications have been described in the past. We describe a new inferior turbinate reduction technique performed with powered instrumentation and assess its success and complication rates. STUDY DESIGN: A prospective study of 120 consecutive patients who underwent submucous resection of the inferior turbinates with a microdebrider. METHODS: Patient questionnaires were used for subjective assessment of symptoms before and after the procedure. We graded each patient's inferior turbinates for size from I to III before and 6 weeks after surgery for objective analysis. RESULTS: The common complications of standard submucous resection of inferior turbinates include excessive resection, postoperative bleeding, and crusting. The advantage of the microdebrider technique is the precise control of the amount of tissue and location of tissue that is removed on a submucosal plane. The complications encountered with this technique are limited to postoperative bleeding that occurred in 1.6% of patients. There was no crusting or excessive removal of tissue. CONCLUSION: The results show that submucous resection of inferior turbinates with a microdebrider is a safe method of achieving turbinate size reduction with minimal morbidity.

Adult↗
PubMed1999

Clinical predictors of obstructive sleep apnea.

OBJECTIVE: To identify physical findings that can be standardized to predict the presence and the severity of obstructive sleep apnea (OSA). STUDY DESIGN: One hundred seventy-two patients who answered questionnaires with responses that suggested they might have OSA were included in this prospective study. METHODS: All patients underwent a physical examination and polysomnography. The physical examination included the measurement of four parameters used by anesthesiologists to identify patients likely to have difficult intubation to determine if these same parameters predict OSA. We recorded modified Mallampati grade (MMP), tonsil size, and body mass index (BMI) and measured thyroid-mental distance (TMD) and hyoid-mental distance (HMD) in the study population. RESULTS: When the physical findings were correlated singly with the respiratory disturbance index (RDI), we found that MMP (P < .001), tonsil size grading (P = .008), and BMI (P = .003) were reliable predictors of OSA. A greater correlation with OSA emerged when an "OSA score" was formulated by factoring the MMP, tonsil grade, and BMI grade (RDI = 7.816 x MMP + 3.988 x Tonsil Size + 4.675 x BMI - 7.544). A high score was not only predictive of OSA but also correlated well with OSA severity. Neither HMD nor TMD correlated with the severity of RDI. CONCLUSIONS: An OSA score may help identify those patients who should have a full sleep evaluation.

Adolescent↗
PubMed1999

Exacerbation of bleomycin-induced lung injury in mice by amifostine.

Bleomycin (BLM) induces lung injury and fibrosis in the murine lung and enhances tumor necrosis factor (TNF)-alpha and collagen mRNA expression in the murine lung. Amifostine is a cytoprotective agent that protects normal tissues from the cytotoxic effects of chemo- and radiation therapy. We investigated the effect of amifostine in BLM-induced lung injury in mice. Mice received intraperitoneal amifostine (200 mg/kg) 30 min before and/or 1, 3, and 7 days after an intratracheal injection of saline or BLM (4 U/kg). The animals were killed 14 days after BLM exposure, and their lungs were studied for TNF-alpha and collagen mRNA expression, hydroxyproline content, and histopathology. Light microscopy demonstrated that amifostine exacerbated the BLM-induced lung injury in mice. Increased TNF-alpha mRNA expression as a result of BLM exposure was not modulated by amifostine treatment. In contrast, amifostine treatment enhanced the BLM-induced expression of alpha(1)(I) procollagen mRNA in the lung. Similarly, mice treated with amifostine before BLM exposure accumulated significantly higher amounts of hydroxyproline (111 +/- 5 microg/lung) than BLM-treated animals (90 +/- 6 microg/lung). These data suggest that amifostine treatment exacerbates BLM-induced lung injury in mice.

Amifostine↗
PubMed1999

Induction of inflammatory mediators in human airway epithelial cells by lipid ozonation products.

We have proposed that exposure of epithelial cell membrane lipids in the lung (mainly phospholipids) to ozone will generate lipid ozonation products (LOP), which could be responsible for the proinflammatory effects of ozone. The ozonation of phosphocholine, the principal membrane phospholipid, produces a limited number of LOP, including hydroxyhydroperoxides and aldehydes. We now report that exposure of cultured human bronchial epithelial cells to the ozonized 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) product, 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (PC-ALD), a phospholipase A(2) (PLA(2))-stimulatory LOP, resulted in a 113 +/- 11% increase in the amounts of tritiated platelet-activating factor ((3)H-PAF) released apically. (3)H-PAF release was also induced by 1-hydroxy-1-hydroperoxynonane of ozonized POPC (HHP-C9), a phospholipase C (PLC)- stimulatory LOP (134 +/- 40% increase in (3)H-PAF). PC-ALD at 10 microM, but not HHP-C9, induced a 127 +/- 24% increase in prostaglandin E(2) (PGE(2)) release (n = 6, p < 0.05). In contrast, HHP-C9, but not PC-ALD, induced interleukin (IL)-6 release (178 +/- 23% increase, n = 6, p < 0.05) and IL-8 release (101 +/- 23% increase, n = 8, p < 0. 05). These results suggest that LOP-dependent release of proinflammatory mediators may play an important role in the early inflammatory response seen during exposure to ozone.

Alkanes↗
PubMed1999

Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice.

We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several varieties of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after exposure to bleomycin or silica, respectively, for TNF and TNF receptor (TNFR) messenger RNA (mRNA), hydroxyproline content, and histopathology. Silica induced increased (over saline-treated animals) expression of TNF mRNA in double TNFR knockout (Ko), C57BL/6, BALB/c, and 129/J mice. In contrast, bleomycin increased expression in all but BALB/c mice, which are resistant to the fibrogenic effects of this drug. mRNA expression of both receptors was constitutively expressed in all of the normal murine strains. Silica upregulated expression of the p75 receptor, but not the p55 receptor, in the C57BL/6, BALB/c, and 129/J mice. In comparison, bleomycin had little effect on either receptor in the bleomycin-resistant BALB/c mice. Hydroxyproline content of the lungs after treatment followed this same pattern, with significant increases caused by silica in the C57BL/6, BALB/c, and 129/J mice, whereas bleomycin caused no apparent increases in the BALB/c mice. Even though silica and bleomycin induced increases in TNF in the TNFR Ko mice, the mice were protected from the fibrogenic effects of these agents. This study supports the concept that TNF is a central mediator of interstitial pulmonary fibrosis.

Animals↗