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C Jiang

Publications and source records attributed to C Jiang.

At least 145 records · Page 8Linked to original sources
PubMed1997

Fluid transport across cultures of human tracheal glands is altered in cystic fibrosis.

1. There is evidence that defective submucosal gland secretion contributes to the airway pathology of cystic fibrosis (CF). Using a capacitance probe technique, we have compared fluid transport across submucosal gland cultures from individuals with and without CF. 2. Under baseline conditions, approximately 60% of non-CF cultures secreted fluid; the rest absorbed. In secreting tissues, amiloride increased secretion, whereas in absorbing tissues it reduced or reversed absorption. 5-Nitro-2(3-phenylpropylamino)-benzoate (NPPB) a blocker of the CF transmembrane conductance regulator (CFTR), converted secretion to absorption. Thus, the direction and magnitude of baseline fluid movement depended on a balance between active absorption of Na+ and cAMP-dependent secretion of Cl-. 3. 8-(4-Chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP), methacholine and luminal uridine 5'-triphosphate (UTP) all induced or increased fluid secretion across non-CF cultures. Results with NPPB and with 4,4'-diisothiocyanatostilbene-2,2'-disulphonate (DIDS), a blocker of Ca(2+)-activated Cl- channels, suggested that fluid secretion induced by CPT-cAMP was mediated primarily by CFTR; UTP acted entirely via Ca(2+)-activated Cl- channels, and methacholine activated both pathways. 4. All CF cultures showed baseline fluid absorption, which was abolished by amiloride. 5. CF cultures showed a normal secretory response to UTP, a reduced response to methacholine, and no response to CPT-cAMP. 6. Thus, the absorptive processes of airway glands are retained in CF, but the cAMP-dependent secretory process is lost. This would markedly reduce the water content of gland secretions. The resulting change in viscosity would contribute to the accumulation of airway mucus which is characteristic of this disease.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Increased contact time improves adenovirus-mediated CFTR gene transfer to nasal epithelium of CF mice.

Multiple dosing with recombinant adenoviral vectors containing the cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the nasal mucosa of cystic fibrosis (CF) transgenic mice reportedly results in only partial correction of the CF defect in chloride (Cl-) secretion without normalizing sodium (Na+) hyperabsorption, perhaps indicating inefficient gene transfer into the nasal airway epithelium in vivo. In this study, we have examined whether optimizing vector administration such as contact time could improve gene transfer efficiency. Changes in basal nasal potential difference (PD), and in PD (delta PD) following addition of amiloride and subsequent removal of Cl- from the luminal perfusate were assayed. As reported previously, the basal nasal PD was significantly more negative in CF mice (-24.9 +/- 2.1 mV) than in normal mice (-6.3 +/- 1.2 mV). Normal mouse nasal mucosa exhibited a large hyperpolarization in response to low Cl- substitution (delta PD of 8.5 +/- 1.9 mV), whereas the nasal mucosa of the CF mouse depolarized in response to this treatment. No correction of either the Cl- or Na+ transport defects were observed when 5 x 10(9) IU of Ad2/CFTR-5 were administered to the nasal passage of CF mice over a period of 5-20 min. However, when CF mice were perfused over a period of 60 min with the same dose of vector, a significant response (delta PD of 5.9 +/- 1.1 mV) to low Cl- substitution was detected 2 days later. In these mice, the basal nasal PD (-10.5 +/- 1.4 mV) and the response to amiloride were also reduced, indicating a partial correction of the Na+ transport defect. Expression of functional CFTR activity was transient with no measurable delta PD signals observed by day 7 post-treatment. These results suggest that prolonging the contact between an adenoviral vector and the respiratory epithelium enhances the efficiency of gene transfer and can result in improved correction of the CF Na+ and Cl- ion transport defects. Therefore, strategies that improve internalization of viral vectors and that prolong their contact time with target cells may result in the improved clinical efficacy of such vectors.

Adenoviridae↗
PubMed1997

Basis of pulmonary toxicity associated with cationic lipid-mediated gene transfer to the mammalian lung.

Studies have indicated that although abundant levels of transgene expression could be achieved in the lungs of mice instilled with cationic lipid:pDNA complexes, the efficiency of gene transfer is low. As a consequence, a relatively large amount of the complex will need to be administered to the human lungs to achieve therapeutic efficacy for indications such as cystic fibrosis. Because all cationic lipids exhibit some level of cytotoxicity in vitro, we assessed the safety profile of one such cationic lipid, GL-67, following administration into the lungs of BALB/c mice. Dose-dependent pulmonary inflammation was observed that was characterized by infiltrates of neutrophils, and, to a lesser extent, macrophages and lymphocytes. The lesions in the lung were multifocal in nature and were manifested primarily at the junction of the terminal bronchioles and alveolar ducts. The degree of inflammation abated with time and there were no apparent permanent fibrotic lesions, even in animals that were treated at the highest doses. Analysis of the individual components of the complex revealed that the pulmonary inflammation was primarily cationic lipid-mediated with a minor contribution from the neutral co-lipid DOPE. Associated with the lesions in the lungs were elevated levels of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) that peaked at days 1-2 post-instillation but resolved to normal limits by day 14. Total cell counts, primarily of neutrophils, were also significantly elevated in the bronchoalveolar lavage fluids of GL-67:pDNA-treated mice between days 1 and 3 but returned to normal limits by day 14. No specific immune responses were detected against the cationic lipid or plasmid DNA in mice that had been either instilled or immunized with the individual components or complex, nor was there any evidence of complement activation. These studies indicate that a significant improvement in the potency of cationic lipid:pDNA formulations is desirable to minimize the toxicity associated with cationic lipids.

Administration, Intranasal↗
PubMed1997

Cloning and characterization of the 5' flanking region of the stem cell factor gene in rat Sertoli cells.

In order to elucidate the molecular basis of stem cell factor (SCF, or steel factor/kit ligand) expression in Sertoli cells of rat testis, 1.5 kb of the 5' flanking region of the SCF gene was isolated and characterized. The transcriptional start point (tsp) was identified by primer extension assay and a rapid amplification of cDNA ends (RACE) assay. A TATA box was found 29 base pairs (bp) upstream from the tsp, and a number of transcription factor consensus sequences, including several AP2 and Spl sites, were identified. The transcriptional activity of the 1.5 kb 5' flanking region was analyzed by deletion constructs using a firefly luciferase-encoding gene (luc) expression vector transiently transfected into primary rat Sertoli cells and other SCF positive and negative cell lines. For all the cells and cell lines examined, a -119 bp to +43 bp fragment including the tsp was sufficient for SCF promoter activity, and the core promoter activity was not significantly changed by inclusion of upstream sequences as far as -1461 bp. These results indicate that additional sites outside of this promoter region are needed to define the cell-specific regulatory elements of SCF expression. The transcriptional activities of all SCF deletion constructs treated with cyclic adenosine 3',5'-monophosphate (cAMP) and forskolin were increased two- to threefold, indicating that SCF transcription in Sertoli cells is regulated by a cAMP-dependent pathway in the proximal promoter region.

3T3 Cells↗
PubMed1997

The analgesic domain of IL-2.

Human recombinant interleukin-2 (IL-2) has been showed to exert an analgesic effect and some experiments suggested that opioid receptors were involved. Because the aromatic residues at the N-termini of opioid peptides are crucial for their binding to the opioid receptors, all nine aromatic residues in IL-2 were mutated by site-directed mutagenesis and both the analgesic activity and the immune activity of the wild-type and mutated IL-2 were tested. The result indicated that there exists a putative analgesic function domain in IL-2, in which Phe44, Tyr45, Tyrl07, and Phell7 were essential. These four residues are located close together at the tertiary structure level of IL-2.

Analgesics↗
PubMed1997

Sulfone metabolite of sulindac inhibits mammary carcinogenesis.

Sulindac sulfoxide, a commonly prescribed anti-inflammatory drug, has cancer chemopreventive activity. During its metabolism, the inactive prodrug sulindac sulfoxide undergoes either reduction to the active anti-inflammatory metabolite sulindac sulfide or irreversible oxidation to sulindac sulfone, which lacks prostaglandin synthetase inhibitory activity. Interestingly, sulindac sulfone has been reported to have cancer chemopreventive activity. The objective of the experiments reported here was to investigate the chemopreventive activity of sulindac sulfone against mammary carcinogenesis and to study its mechanism. Rats were injected with either 12.5 or 37.5 mg of 1-methyl-1-nitrosourea (MNU)/kg body weight at 50 days of age. Sulindac sulfone was incorporated into a purified diet at a concentration of either 0.03 or 0.06% (w/w) and fed to rats beginning 7 days after the injection of MNU. Sulindac sulfoxide at a level of 0.06% (w/w) was fed as a reference for comparison. Thirty rats were assigned to each dietary group treated with the high dose of MNU, and 44 rats were assigned to each dietary group treated with the low dose of MNU. The sulfone reduced cancer incidence and the number of cancers per rat irrespective of the dose of MNU injected, and its chemopreventive activity was comparable to that of sulindac sulfoxide. Cancer latency was also prolonged significantly by sulindac sulfone; the effect was particularly notable at the low dose of carcinogen, at which the prolongation of latency was >8 weeks. The sulfone inhibited the occurrence of mammary carcinomas that were classified as having either a wild-type or a mutant codon 12 in the Ha-ras gene; however, the inhibitory effect was greater against carcinomas with a mutant Ha-ras genotype. Using a mammary gland organ culture transformation assay, it was observed that sulindac sulfone also inhibited the formation of 7,12-dimethylbenz(a)anthracene-induced hyperplastic alveolar nodules and that the inhibitory activity of the sulfone was comparable to that of the sulfoxide. These data indicate that the observed effect of the sulfone on mammary carcinogenesis in vivo is likely to be due to a tissue-specific effect rather than to other systemic effects. The findings that both the prodrug and the sulfone inhibited carcinogenesis in vivo and nodule formation in organ culture and that the sulfone lacks inhibitory activity on prostaglandin synthesis suggest a mechanism(s) of chemoprevention that is independent of the prostaglandin pathway. A candidate mechanism for the apparent clonal selection pressure exerted by the sulfone against mammary carcinogenesis is apoptosis. To test this hypothesis, MCF-7 cells were exposed to a range of concentrations of sulindac sulfone and sulfoxide. Both compounds inhibited cell growth and induced apoptosis in the absence of necrosis. Collectively, these data support a specific chemopreventive effect of sulindac sulfone against mammary carcinogenesis and indicate that this compound may have a selective effect against carcinogenesis involving alterations in the signal transduction cascade of which Ha-ras is a component. Evidence is consistent with the involvement of apoptosis in the cancer-inhibitory activity observed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Novel saponins hainaneosides A and B isolated from Marsdenia hainanensis.

Novel saponins possessing fertility-regulating activity, hainaneosides A (1) and B (2), have been isolated from the twigs and stems of Marsdenia hainanensis, and their structures have been elucidated unambiguously as 12-nicotinoyl sarcostin-3-O-beta-D-glucopyranosyl-(1-->4)-3-O-methyl-6-deoxy-bet a-D- allopyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta-D- cymaropyranosyl-(1-->4)-beta-D-cymaropyranoside and 12-nicotinoyl-20-cinnamoyl sarcostin-3-O-beta-D-glucopyranosyl-(1-->4)-3-O-methyl-6-deoxy-bet a-D- allopyranosyl-(1-->4)-beta-D-oleandropyranosyl-(1-->4)-beta-D-c ymaropyranoside using NMR spectroscopic techniques and chemical transformations.

Abortifacient Agents, Nonsteroidal↗
PubMed1997

Depsipeptide (FR901228, NSC-630176) pharmacokinetics in the rat by LC/MS/MS.

Depsipeptide, a cyclic peptide (FR), isolated from Chrombacterium violaceum strain WB968 by Fujisawa Company during a screening program for anti-oncogene agents, possesses potent antitumor activity against human tumor cell lines and xenografts. This compound has been selected for preclinical and early clinical development by the National Cancer Institute. The pharmacokinetics and oral bioavailability of this depsipeptide in the rat were investigated in the present study. A sensitive and specific electrospray LC-tandem mass spectrometry method was first developed and validated for the analysis of this depsipeptide in plasma using t-boc-alpha-d-glutamic acid benzyl ester as the internal standard. The routine sensitivity limit was 1 or 10 ng/ml using 1.0 or 0.1 ml of plasma sample. The within-run CV values were 11.8, 17.9, 11.0, and 5.0% at 1, 10, 100, and 500 ng/ml levels, respectively, with corresponding accuracy of 94.4, 109, 95, and 97% (all n = 6). A formulation based on ethanol, normal saline and PEG400 was then developed and Fischer rats were given this formulated drug separately by intravenous and oral route. Plasma drug concentrations were measured by this method and pharmacokinetics were analyzed by the standard techniques. Plasma concentration-time profiles were found to follow a biexponential decline with a mean terminal t1/2 of 97 min and mean total clearance (CLt) of 425.3 ml/min/kg following i.v. dosing at 10 mg/kg. Following oral dosing at 50 mg/kg, the peptide was absorbed but produced erratic drug levels also with a bioavailability of 15.6%. Thus, active plasma concentrations can be produced up to 3 hrs in the rat following a single dose at 10 mg/kg and the peptide represents one of the very few orally absorbed peptides reported.

Administration, Oral↗
PubMed1997

Mapping quantitative trait loci with dominant and missing markers in various crosses from two inbred lines.

Dominant phenotype of a genetic marker provides incomplete information about the marker genotype of an individual. A consequence of using this incomplete information for mapping quantitative trait loci (QTL) is that the inference of the genotype of a putative QTL flanked by a marker with dominant phenotype will depend on the genotype or phenotype of the next marker. This dependence can be extended further until a marker genotype is fully observed. A general algorithm is derived to calculate the probability distribution of the genotype of a putative QTL at a given genomic position, conditional on all observed marker phenotypes in the region with dominant and missing marker information for an individual. The algorithm is implemented for various populations stemming from two inbred lines in the context of mapping QTL. Simulation results show that if only a proportion of markers contain missing or dominant phenotypes, QTL mapping can be almost as efficient as if there were no missing information in the data. The efficiency of the analysis, however, may decrease substantially when a very large proportion of markers contain missing or dominant phenotypes and a genetic map has to be reconstructed first on the same data as well. So it is important to combine dominant markers with codominant markers in a QTL mapping study.

Algorithms↗
PubMed1997

The apoptosis of HEL cells induced by hydroxyurea.

Hydroxyurea has been used to synchronize cultured cells to S-phase and used to treat patients with sickle-cell anemia. Recently, we found that hydroxyurea can induce the apoptosis of HEL (human erythroleukemia) cells. The induced HEL cells showed ultrastructurally chromatin condensation with regular crescents at the nuclear edges and apoptotic bodies. However, the cells of K562, another human erythroleukemia cell line, did not show such morphological changes. Under fluoroscope, the HEL cells after induction often displayed a clear reduction in nuclear diameter and nuclear chromatin cleavage and condensation and the presence of nuclear ring and apoptotic bodies. Analysis with flow cytometry showed that the percentage of apoptotic cells is about 30-40% after HEL cells were induced by hydroxyurea for 3 days. DNA ladder can be observed by electrophoretic analysis.

Apoptosis↗
PubMed1997

Visualization of chromatin folding patterns in chicken erythrocytes by atomic force microscopy (AFM).

The organization of the higher order structure of chromatin in chicken erythrocytes has been examined with tapping-mode scanning force microscopy under conditions close to their native environment. Reproducible high-resolution AFM images of chromatin compaction at several levels can be demonstrated. An extended beads-on-astring (width of approximately 15-20 nm, height of approximately 2-3 nm for each individual nucleosome) can be consistently observed. Furthermore, superbeads (width of approximately 40 nm, height of approximately 7 nm) are demonstrated. Visualization of the solenoid conformation at the level of 30 nm chromatin fiber is attained either by using AFM or by using electron microscopy. In addition, tightly coiled chromatin fibers (approximately 50-60 nm and approximately 90-110 nm) can be revealed. Our data suggest that the chromatin in the interphase nucleus of chicken erythrocyte represents a high-order conformation and AFM provides useful high-resolution structural information concerning the folding pattern of interphase chromatin fibers.

Animals↗
PubMed1997

Trans-acting factors from the human fetal liver binding to the human epsilon-globin gene silencer.

The developmental stage-specific silencing of the human epsilon-globin gene during embryonic life is controlled, in part, by the silencer (-392 bp approximately -177 bp) upstream of this gene. In order to elucidate its role, the nuclear extract from the human fetal liver has been prepared and the interactions between trans-acting factors and this silencer element have been examined. By using DNaseI footprinting assay, a major protected region from -278 bp to -235 bp within this silencer element was identified. Furthermore, we found in gel mobility shift assay and Southwestern blotting assay that there were at least four trans-acting factors (MW approximately 32, 28, 26 and 22 kD) in the nuclear extract isolated from the human fetal liver, which could specifically bind to this region. Our results suggested that these trans-acting factors might play an important role in silencing the human embryonic epsilon-globin gene expression at the fetal stage through the interactions with this silencer.

Binding Sites↗
PubMed1997

Immortalized mouse mammary cells in vivo do not exhibit increased telomerase activity.

The acquisition of immortalization is an early and carefully documented event in mouse mammary tumorigenesis. Activation of telomerase activity is one hypothesis to explain the acquisition of immortalization. We examined the activity of telomerase in well-defined immortalized, non-tumor cell populations of mouse mammary tissue in vivo. The results indicated that normal virgin and mid-pregnant mammary gland had low to moderate levels of telomerase activity, respectively. In comparison with the levels detected in pregnant mammary gland, telomerase activity was elevated in mammary tumors in situ and in established mammary cell lines in vitro, both tumorigenic and nontumorigenic; however, hyperplastic alveolar preneoplastic mammary outgrowths and non-tumorigenic ductal outgrowths, both in vivo immortalized populations, had telomerase activity <12% of the levels detected in normal pregnant mammary gland. These results suggest that elevated telomerase activity is not necessary for the immortalization phenotype in in vivo mouse mammary cell populations and that elevated telomerase activity occurs as a late event in mammary tumorigenesis. Furthermore, the data suggest that low levels of telomerase activity are characteristic for mouse mammary epithelial cells and not sufficient for immortalization. These data suggest that other factors play more important roles in the induction and/or maintenance of the immortalization state in mammary cell populations.

Animals↗
PubMed1997

Retention of conjugated linoleic acid in the mammary gland is associated with tumor inhibition during the post-initiation phase of carcinogenesis.

Conjugated linoleic acid (CLA) has been reported to have significant activity in inhibiting mammary carcinogenesis. A major objective of this study was to evaluate how changes in the concentration of CLA in mammary tissue as a function of CLA exposure/withdrawal were correlated with the rate of occurrence of mammary carcinomas. Rats treated with a single dose of dimethylbenz[a]anthracene (DMBA) at 50 days of age were given 1% CLA in the diet for either 4 weeks, 8 weeks or continuously following carcinogen administration. No cancer protection was evident in the 4 or 8 week-CLA treatment groups. Significant tumor inhibition was observed only in rats that were given CLA for the entire duration of the experiment (20 weeks). Analysis of CLA in the mammary gland showed that the incorporation of CLA was much higher in neutral lipids than in phospholipids. When CLA was removed from the diet, neutral lipid- and phospholipid-CLA returned to basal values in about 4 and 8 weeks, respectively. The rate of disappearance of neutral lipid-CLA (rather than phospholipid-CLA) subsequent to CLA withdrawal paralleled more closely the rate of occurrence of new tumors in the target tissue. It appears that neutral lipid-CLA may be a more sensitive marker of tumor protection than phospholipid-CLA. However, the physiological relevance of CLA accumulation in mammary lipids is unclear and remains to be determined. A secondary goal of this study was to investigate whether CLA might selectively inhibit clonal expansion of DMBA-initiated mammary epithelial cells with wild-type versus codon 61 mutated Ha-ras genes. Approximately 16% of carcinomas in the control group (without CLA) were found to express codon 61 ras mutation. Although continuous treatment with CLA reduced the total number of carcinomas by 70%, it did not alter the proportion of ras mutant versus wild-type carcinomas, suggesting that CLA inhibits mammary carcinogenesis irrespective of the presence or absence of the ras mutation.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

An adenosine deaminase (ADA) allele contains two newly identified deleterious mutations (Y97C and L106V) that interact to abolish enzyme activity.

Genetic deficiency of the purine salvage enzyme adenosine deaminase (ADA) results in varying degrees of immunodeficiency, ranging from neonatal onset Severe Combined Immunodeficiency (SCID) to an adult onset immunodeficiency disorder. Multiple different mutations have now been identified in these immunodeficient patients. Additional mutations, initially identified in healthy individuals, abolish ADA in erythrocytes but retain 10-80% of activity in non-erythroid cells ('partial deficiency mutations'). In general, severity of disease correlates inversely with the amount of residual ADA expressed by the mutant enzymes and directly with the accumulation of the toxic metabolites deoxyATP and deoxyadenosine. We report two newly identified mutations (Y97C and L106V), both carried on the same allele of an immunodeficient patient who was diagnosed prenatally and successfully transplanted with haploidentical bone marrow. Based on the ability of mutant cDNAs to express ADA in vitro , the L106V mutation resulted in activity similar to 'partial' mutations (30% of normal) while the Y97C mutation resulted in detectable but markedly reduced activity (1.5% of normal). However, the presence of both mutations on the same allele virtually abolished detectable enzyme activity. Analysis of the crystallographic structure of ADA to understand the marked deleterious effect of the Y97C mutation suggested a previously unappreciated role of salt bridges in the catalytic mechanism of ADA. The patient was also heteroallelic for a previously described deletion of the promoter and exon 1. Testing of additional patients in whom we had not identified a mutation on the second allele revealed presence of this deletion in three of four patients tested. This deletion is therefore relatively common, accounting for 10% of almost 100 chromosomes studied by this and other laboratories, but is easily missed by currently used methods of mutation detection. Lastly, the finding of two mutations on the same allele that interact to reduce residual enzyme function emphasizes hazards in evaluating potential genotype-phenotype correlations in individuals analyzed only for the presence of single specific mutations.

Adenosine Deaminase↗
PubMed1997

Differentiation of Helicobacter pylori strains directly from gastric biopsy specimens by PCR-based restriction fragment length polymorphism analysis without culture.

Recent studies have shown the usefulness of PCR-based restriction fragment length polymorphism (RFLP) analysis for differentiating Helicobacter pylori strains isolated by culture. For this study, a PCR-based RFLP assay was developed for directly typing H. pylori strains from gastric biopsy specimens. Nineteen gastric biopsy specimens obtained from patients undergoing endoscopy for gastrointestinal complaints were cultured for isolation of H. pylori. Genomic DNA preparations from these gastric biopsy specimens and the corresponding H. pylori isolates were tested by our PCR-based RFLP assay. The 1,179-bp H. pylori DNA fragments amplified by the PCR assay were digested with the restriction enzymes HhaI, MboI, and AluI and analyzed by agarose gel electrophoresis. HhaI, MboI, and AluI digestion produced 11, 10, and 6 distinguishable digestion patterns, respectively, from the 19 H. pylori isolates tested and generated 13, 11, and 6 different patterns, respectively, from the 19 gastric biopsy specimens. The patterns from 13 of the 19 gastric biopsy specimens matched those of the H. pylori isolates from the corresponding patients. The patterns from the remaining six biopsy specimens appeared to represent infection by two strains of H. pylori; the pattern of one strain was identical to that of the isolate from the corresponding patient. By combining all the restriction enzyme digestion patterns obtained by using HhaI, MboI, and AluI, we observed 19 distinct RFLP patterns from the 19 specimens. The results suggest that the PCR-based RFLP analysis method may be useful as a primary technique to identify and distinguish H. pylori strains directly from gastric biopsy specimens without culture of the organisms.

Bacterial Typing Techniques↗
PubMed1997

O2-sensing mechanisms in excitable cells: role of plasma membrane K+ channels.

Although carotid chemosensitive glomus cells have been the most extensively studied from the vantage point of how cells sense the lack of O2, it is clear that all tissues sense O2 deprivation. In addition, all mammalian cells can trigger a cascade of events that, depending on the severity and duration of hypoxia-induced stress, can lead to permanent injury and death or to adaptation and survival. Crucial in this cascade, we believe, how the cascade is initiated, how O2 lack is detected by cells, and how these initial steps can activate further processes. In this chapter, we focus on the initial steps of O2 sensing in tissues most commonly studied, i.e. carotid glomus cells, central neurons, smooth muscle cells, and neuro-epithelial bodies of the airways. Recently it has become clear that plasma membranes of various tissues can sense the lack of O2, not only indirectly via alterations in the intracellular milieu (such as pH, Ca, ATP, etc), but also directly through an unknown mechanism that involves plasma-membrane K channels and possibly other membrane proteins. This latter mechanism is suspected to be totally independent of cytosolic changes because excised patches from plasma membranes were used in these experiments from carotid cells and neurons. There are a number of questions in this exciting area of research that pertain to the role of this plasma-membrane O2-sensing mechanism in the overall cell response, identification of all the important steps in O2 sensing, differences between O2-tolerant and O2-susceptible cells, and differences between acute and chronic cell responses to lack of O2.

Animals↗