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dialinguish diiferences between noncanaer nd lung cancer patients. In non- cancer patients, there is a good agreement between values for Alllt in fresh PAM and cultured lymphocytea; however, when similar menurements are compared in individual lung cancer patients, the AHH values in cells from the two diRereot tissues are dissociated. Since this diuociation between AIIlI levels is consistently found in lung cancer patients, a comparison between Alilt kvels in cultured PAM and lymphocytes could be of diagnostic aid when lung cancer is suspected. Mcl.emore, T. 1.., Alarrin, R. A.. Wray, N. P.. Cantrell, E. T., and Busbee, t). 1.. Cancer Research 38 (11) :)d01-le 11, 1978. Ot6er awrrorlr National Inslilutea of Health, American Cancer Society and the Veterans Adndnis/ralion Hoapilal, Houston. From the (kp.nments of Medicine and Microbiology and Immunology, Bay- lor College of Medicine, and Veterans Administration Hospital. Houston; the Deparlmenl of Biological Sciences and the Genetka Center, North Texas Slate Universily, Denton• and the Department of Pharmacobp, Texas College of Osteopathic Medicine, Fort Worth. EFFFCTS OF SNLFNIUM ON ARYI. IIYDROCARBON HYDROXYI.ASE ACTIVI"IY IN CULTURNI) IIUMAN LYMPHOCYTES This paper examines the effects of aeknium (Se) on induction of aryl hydrocarbon hydrosylaae ( AI1H ) activity in lymphocyte cultures and on the enzyme activity itsetf. Esperimen1a11y, human lymphocytes were cultured both In the presence and absence of induun of AHH. The presence of 10' M Se during the IaN 24 hrs. of culture (corresponding to the time when inducer was present) or during the entire culture period had no inhibitory eRect on AIIH activity in eilber eoninduced or Induud cells. However, the presence of Se in the assay ilself inhibited AHH activity by more than 50%. This level of inhiAition was seen at concentrations of the aubslrate benzo(alpyrene of 1, 3, 10, and 100 pm and Se concentrations of 0.1. 0.), 1, and 10mM, respectively. Interestingly enougA, when AI(It activity was measured In noninduced celis in the presence of low concentrations of Se, the All/t activity was slightly higher than when Se was absent. These findings Indicate that the inhibitory cfkcl of Se on tumorigenesis in• sludies with several experimental animal sya- lems may he explained in part by the inhibition of microsomal osidases re- spomibk for metabolic conversion of precarcinogens to ullimate, ekclrophilic earcinogens. Rasco. M. A.• lacobs, M. M. and OriBn, A. C. Cancer Lrtttrs ):29S-101, 1977. Other aupportr National Cancer Institute. Frum the thparlmcws of Biology and Bachemistry, Ihe llniversity of Tctas Sy.tem ('ancer ('entcr, M 1) Anderson llospital and Tumor Inslilute, IIoNn1on. OALACTOSYL TRANSFERASE IN BENIGN AND NEOPLASTIC HUMAN BI.ADIJeR MUCOSA ~ Uridine S'-diphoaphale Ralaclose:Rlycoprottin plac/osyl Iraesferaae (Oal- X), an enzyme which is involved in the bioaynlhesis of complex carbohydrates of cell membranes, has been implicated in intercellular recoRnilion, adhesion and di/ferentiation, and associated with some human endodermally derived tumon. In the present study of the activity of Gal-X in human transitional cell carcirwma, the homojenales of four established tranailional cell carcinoma lines (MG11-1, MOII-2, RT-1, and T-24) were shown to have signifkanUy increased (3al-X activities as compared with human Abroblasts in tissue culture. Because of thia, pal-X activity was then studied in fresh specimem of benign. Irdlamed, and neoplwic human bladder epithelium. Reaulu showed that 40 waya on transitional cell carcirsonsa, both invasive and raninvaaive, ranged from 24.4 to 180.0 cpm/rR of protein (mean 70.)), and SO uuya on normal or inflamed mucosa ranged (rom 0.0 to 46.1 cpm/r= (mean 9.00). 7he nsa- tority of benign mucosal specimens showed aorne inflammatory chanRea, but that did not increase the level of Oa1-X activity. These results, which show that human transiliond cell carcinoma has increased (ial-X activity regardless of tumor staRe or grade as compared with benign transitional cell epilhelium, Indicate that this increase may be useful in the development of diagnostic /luoroimmune and radioimmune techniques to ddect transitional cell carcinoma. Ilagen-Cook, K., Prout, O. R.. Ir., Plotkin, O. M., Oilbert, S. 1.., and WolJ G. Surgical Forum 29:627-629, 1979. Other aurportt National Cancer In.tilule. From the Urological Service. Massachusetts General Hospital, and the Depart- ment of Sur`ery, Harvard Medical School, Boston; and the Departmeot of Nutrition and Food Scienct, Massachusetts Imtilute of Technolop, CambridRe. I CYCLOPI/OSPHAMIDE-INDUCED ONCOOENIC TRANSFORMATION. CHROMOSOMAL BREAKACIE, AND SISTER CHROMATID EXCIIANGE FOLLOWING MICROSOMAL ACTIVATION Cancer chemotherapeutic agenta may be unequaled for the purpose of • assessing short-Ierm mammalian tissue culture assay aystems for their actual ability to predict human risk of developing cancer as a result of exposure to certain compounds. ihia paper illustrates that while cyclophosphamide does not produce oncogenic transformation in the absence of a metabolic activation aystem• sienifkant transformation does take place in Ihe presence of an exo2tneous activation source. Cell culture with and without an esogrnous liver metabolic activation system was used to investigate the eR.ct of this chemotherapeutic agent on oncogenic transformation and ehrorno.ord.l damage, including increased sister chrrKnali) exchanges. As noted above• cyclopho.- peamid- did not produce any abnormalities in the absence of metabolic ac- 17 16

tlvation, but incorporation of the activating system into the assays kd to significant tranaformalion, chroawsomal breaka and increasea in sister chroma- tid e.chantes. lhe removal of glucose-6-phoaphate nd nicotinamide adenine dinuckolide phosphate from the metabolic generating system, however, com- pktcly eliminated these aberrations. According to these retults, it may be necessary to incorporate some activation procedure into any suudy utilizing in vitro systems to determine the potential human hazards of a particular ehemical. Benedfcr, W. F., Banerjoe, A. and Ve.ka/eaan, N. Cancer Research 711:2922-2921, 1972. Prom the Division of Itematobpr-0noo/oRy. Department of Med'v:ine, Chil- dren's Ilospital of Lo. Anaeks; and the Department of Pedlalrics. University of Sixdhern California School of Medkln., Loa Angelea. MIITAGENICITY OF CAN('FR ('HPMOTHERAPEUTIC AGENTS IN 7IIL+ SALM(1NF.t.LA/MICROSOM@ TFST Many short term assays have hoco developed recently to screen potential chemical carcinotrns/mulatens, and cancer chemotherapeutic drugs have been considered partrculaily suitable for esamining the relationships among short term in vbro aaays, in vlvo carcinogenKity studies and chemical carcino- genesis In man. In the present study, 17 cancer chemolherapeutic agents were tested for their ability to mutate Salmoneffa tyoAimurirm lesler strains in the Sa/monrfla/mkrosome mutagenkity test. Results showed a high correlation between the mulagenicity and carcinogenicity of a given agent. Carcinogens positive in the test were adriamycin, daunomycin, 1-propanol-J,7%iminodime- Ihanesulfonate, cyclophosphamide, isophosphamide, hycanthone, chlornaphazin, nitrogen muMard, uraeil mustard, melphalan, and thio-TEPA. Two known earcinogens, aclinomycin D and bkomycin, were not delected as mutagena. 'i1The presumptive noncarci"cn, methotre><ate, was neitative in the lest. How- ever, tilorone and 6-mercaptopurine, tentatively clanifkd as noncarcinogena, were mWagenie. In summary, these Icau showed that 11 of 13 of the chemo- lherapeutie agents that are carcinogenic were also mutagenic in the Safmonelfa/ microwme system. In addition to being carcinogenic in animal studies, some of these agents are suspected of being carcinogenic in man. Benedict. W. F. .r at. Cancer Reua.cb J7:2209-2217, 1977. OtAer support: National Cancer Institute. From rhe f)rvisa.n of 1lemslnlogy and t)ncoloty- tkpartmenl of Medicine, ('hdJren's I/ttipiul, I 0. AnRrlcs, and the Ihpartment o1 IliiKhcmistry, t)ni- vcr%dy ol l.h/ouu., IkArl. v I CEI L CYCLE-SPECIFIC ONCOOENIC TRANSFORMATION OF CI1f/ 10TIA CI.ONE ff MOUSE EMBRYO CELLS BY I-/9-D-ARABINOFU RANOSYLCYTOSINE The drug 1-/l-D-arabinoluranosykytoarse (araC), which Ia widely used as a ehemotherapeulie agen1, is a powerful DNA inhibitor. In mamrnalias cells, it is phosphorylated to the tripho.phate level and subsequently inhibiu replication synthesis in preference to repair synthesis. Earlier studies by various investigalon show that it can also be incorporaled, although not ea- tensively, into DNA. that it produces cell eyck-apeciflc chrornatid breakage, induces chromcraoal abberations, is mutadenic to mammalian cclb, and interferes with the synthesis of gIyeoproleina and filycolipid.. It is also capable of causing malignant tranafo.mation in cultured hamster embryo aBa and in rat cells. Thia report shows that the nuclooaide also inducea oncoscnk transformation In 1he C7H/ IOTK CLtI line of mouse embryo cells and that this Iramformation is primarily S-phaae specific. Cell lines derived from type 111 transformed foci grew in soft agarose and produced tumors in immuno- suppressed aynneneie mice. In cells synchronized by poatconfluent growth inhibition or isokucina deprivalion, transformation was cell cycle dependent. Maaimal tramformation was obiervcd in cells treated In the S phase, although tome transformation occurred in cells treated in the O, phaae. The authors indicate that some of Uese reaulu may be eaplained by the facl that araC is capable of causing ehroanoaornal lesions in the (l, phase and of delaying the entry of O, cells inlo the S phase. They aiso.uggest that specific chromo- aomal ehanges may be particularly important in chemically induced malignant transformation, especially since the eapresaion of cancer in cells transformed by ara-C is associated with specific ehromoaoroal imbalanua. lonea, P. A., Baker, M. S., Bertram, l. S., and Oewedict, W. F. Cancer Re.eareA 77:2214-2217, 1977. . Other a.rpport: National Cancer Institute. From the Division of Hemalology-(Mcolop. Department of Medklne, QiY- dren: Hospilal, l.os Angeks; and the Department of Eaperimental Therapeu- tics, arace Cancer Drug Center, Roswell Park Memorial Institule, BuAab. SPECIFICIIY OF HUMAN. RAT AND MOUSE SKIN EPOXIDtE HYDRATASIi TOWARDS K-RF.OION EPOXIDES OF PULYCY('I.IC HYDROCARBONS Micro.omal enzymes have, the capacity to transfonn aromatic and okbnic compounds (ncludrng benzo/w/pyrene to eposides which are elec- trophilic and can apontaneously form covalent bonds with the nucleophilie moieties of tissue 1)NA. RNA and protein. Several studies have shown that epoaide hyJratase has a unique role in the "tabolic formation of carcino- gens from polycyclic hydrocarhons. llris repixt emrmeralea avme of Ihis enzyme's properties in human, rat and mouse skin mirrnsomal fractrons and compares them to those found in liver preparations 7he skin enrymc hydrated all epoawka tested, with human fraclions showing the most activtty, followed IB • 19

in descending order by mouse and rat samples. The level of activity, however, changed with each of the various polycyclic hydrocarbon. as substrates. In human skin microsomal fractions, the eposide hydratue activity dwwed little p11 dependence and was inhibited by small molecular weight inhibiiors in a manner similar to that of the liver microsomal enzyme. However. tM! activity does seem to vary considerably among individuals, as demonstrated by the skin microsomal fractions of sin humao subjects. Thu variation was not due to skin disease or Ireatment and seemed indepe.dent of age or aes. Tlu enzyme activity in abdominal skin sampks. Iwwever, scemed to be lower Ihao in samples taken from the leg or breaM, suggesting a possible correlation between the activity level and the tissue's sile of origin. According to the re wlts, the enzyme found in skin microsomal (ractiona is Inlrinaically similar lo dut found in liver micro.omal fractiona, so that any data obtained with liver epotide hydralase are mosl probably also applicabla to ski.. Orirh, F., Scbmaaamann. H. and Bentley. P. Biochemical Pharmardogy 27:17-20. 1978. From the Institute of Pharmacology. The University of Mainz, Mainz, West (;ermany. THC ROl f? OF GIiNF:TICS AND HOST FACTORS IN CANCER SUS('EP I IBILTIY AND CANCER RFSISTANCE 7his paper provides a survey of current findings relating to cancer susceptibility and resistance in humans and attempts to apply this knowledge in a meaningful way to clinical medicine in general and to cancer control in particular. Familial cancer distribution In man, geographic variations in cancer susceptibility and tissue susceplibility in hereditary cancer are esamined here as pertinent variables in the overall cancer problem. Such eaampka as carcinoma of lhe brent, colon, von Recklin=hausen's neurofibromatosis, and multiple primary malignant rseoplasms emphasize Ihese variables. One of the most consistent observations in cancer genetiea is the significant eacess of mullipk primary malignant neoplasms in cancer prone families. Problems in genelic heterogeneity and mechanisms involved In biological markera in cancer re carefully considered. While many esampks of cancer suaceptibility are presented for eaansinalion, the likrature contains few inslances of cancer re- siuance. This is unforlunate, since a beller understanding of human cancer resistance might kad to the elucidation of inechanisms which could protect against cancer, inslcad of merely controlling the disease after its onset l.ynrh, It. T. rf al. Canrrr nnrr•rion and Prrvrnrion 1( 1):173-224, 1976. Othrr support: Narw+nal In.ututn of Ilea)rh and the Fralernal Order of 1'ig1e% 1 r..in rhe 14p.rrn.rnr ot 1'rrveMive MrdMrne and Public Fledrh, ('rei`hlon llniVrrvl~ 1.h.rd .-1 A(r.hin.r, t)nuha I GENETIC AND COMMUNICABLE EFFF.C,T$ ON CARCINOEMBRYONIC ANTIGEN EXPRESSIVITY IN THE CANCER FAMILY SYNDROME Carcinoembryonic antigen (CEA ), which hr .hown potential as a mut.r for endodermal cancer (particularly cancer of the colon), was studied her. lo: (a) leat CEA's potential as a discrimioanl of penetie cancer risk in canotr- prone families: (b) quantitate the role of age and duration of cigarette smoking in CEA esprea.bn; and (c) test for connubial effects on CEA is the hereditary cancer family syndrome. To do thia, plasma CEA /erela wera ezamined in 198 relativea and 84 spou.ei of ais carsrxr-prosse kindreda, and in 191 normal controls. The CEA di.tribulion. per as were transformed to square root CEA (VCEA) as a correction for skewness and kurtosis. The snean VCI'A did not differ betwoen cancer family members and controls of the same smoking status. Funhermor., the ratea of change In V('P.A with increasing age and duration of smoking were similar in both cohorts. Ilow- ever, when pedigree data were classified by closeness of relationship to canocr patients there was a siRniflcanl lintar increase in mean VCEA with increasing jenelic risk. Surprisindy. CEA kveb of spouses showed the sanre treod as their direct-genelic-line malea (spouses were classified according to the genetic risk status of their mates rather tha. their own genetic lineage). Among both direct-line relatives and their apouw, there was a consistent linear decline in \/CEA with declining risk Na/w. Inlraelasa eorrelatian of CEA between direct-line relatives and their npouse. approached ,ignilkanoa when both spouses were concordant for smoking status. These data reflect as intricate chain of events htvolving Rendia, eomnwnicability, and physical interactin4 phenonsena. An integrative target cell theory ia proposed here so tsplain CEA espressivity in this syndrome. In the given rnodel, the larlet faclors appear to Interact differeatially at the nsolecular-cellular level to caur CEA varialions. GrlrtL, H. A.. LyncA, H. T., Harris, R. E., and Vandevoorsfe,l. P. Cancer Research 3t({):2527-2521, 1970. Other aupprt: HoQmann-LRoche, Inc., National Cancer Institute. FannM E. Ripple Foundation, and the Fraternal Order of Failkt+. From the Dewrtment of Preventive Medicine and Public Heallh, Creighton University School of Medicine. Omaha; and the Department of Immunobp, HuRmann-LaRoche, Ine., Nutky, N. 1. CARCINOhMBRYONIC ANTI(7F.N (CEA) IN T/IP. CANCER FAMILY SYNDRJ)ME 0 The carcinoemhryonie antigen (CEA) has been described as a marktr for the detection of endodermal cancer, especially malienancy of the colon. This study attempts to furlher elucidate the potential of CEA as a discriminant of cancer risk in kindreds demonstrating ahe Cancer Family Syndrome. Plasma samples were collected from 143 relalives and 65 spouses of sia csncer-prono kindreds, over a pcriud of four years. For statistical eompariaons, rclatives were classified as: (1) cancer patients. (2) unsffec/ed Individuals at high genetic risk (one or more first degree rclatives d(eeted), and (3) unaffected individuals 20 21

at low genetic cancer risk (no Ant-depee rslalives with cancer). Unrelated spouses were assigned the same clan number as their direct-line mate. In cancer patients and relatives at high genetic risk, the mean \/CPA was signifkantly higher than in relatives at low genetic risk. Surprisingly, how- ever, unrelated spouses had mean levels of Y/CPA similar to those in the corresponding risk clau of their direct-line mates. These data suggest that both a genetic and a connubial factor operale on CP-A, the latler presumably traceable to a common environmental aRed actinR in concert with the desrte of genetic predisposition to oncolienesis in this syndrome. These resuits por- tend a hypothesis bascd upon a corntnunkabk-jenelic Interaction involving transformed viruses that oAen a partial esplanation for the genesis and trans- miuion of oncodevelopnuntal prolebr is memben of high cancer risk k indreds. OrLr4, H. A., Lynch. H. T., Ilarris, R. H., and Vandavoorde, 1. P. Canctr I)()):1374-1S7f1, 1978. Other eupportr IloRmann-lARoche, Inc., Roeha Research Center, the Na- tional Cancer Instilute, the Fraternal Order of PaRles and the Fannie E. Rippel Foundation. From the Department of Preventive Medicine/Publie Health. Creighton Uni- vcnity School of Medicine, Omaha; and the Research Division, Depatlrxnt of Immunology. HoRmann-laRoche, Inc., Nutky, N. J. OPNPTIC REOUT ATION OF Sl1SCPPTIBII.f TY TO POLYCYCLIC-IIYDR(X'ARBON INDl1CFI) TUMORS IN THE MObSP The eytochrome P-ISO mediated monoosygenases are a collective ea- ample of Phase-I enzymes which can be regulated in the mouse esperirnental system. These membrane-bound mullkomponent enzyme systems, while re- yuirinR molecular osygen and NADPH, are tnown to metabolize pulycyclk hydrocarhons such as bcnzo[elpyrene (BP), )-melhykholanthrene (MC), biphenyl, elc. While it is now generally accepted that during the detosifkation of these compounds by Phase-I and Phase-11 enzymes, polent reactive inter- mediales, capable of binding covalently with cellular macroreoleeules, can be formed, the association of steady-s/ale levels of certain of these reactive (ntermediates with cancer, mulation, and toakity is presently of great rtsearch Interest. Primarily, the aryl hydrocarbon hydroaylaae (AIIiI) assay Is a reliabk, simple and very sensitive assessment of aromatk hydrocarbon responsiveness following trealment of animals with polycyclic hydrocarbon ieducen Pspcri- mentally, with the use of inbred strains of mice and the appropriale genetic crosses, it was possible to demonstrate that a single al/elk difference or a very smaM number of genes could have a profound Influence on n individual's increased tusceptibility to chemical eareinosenesis, drug toskity, and con- genital maQormate.ns. Ilowever, it was also shown that genes other than Ihe AA locus miRhl influrnce an individual's risk (or lumorigenetis. Aside from the Ah hxus, rhree miNhfyint factors in tumorisenesn Ihat may be of im- p.nlarKe and m.y al+n he undcr Renetic control inchtale ONA repair, vital t.l~tcsau.n. arnl nnrnnnnl,.graa t,.lcr.rnac Ihe inlerpl.y bttween Ihe Ab Inctn and these above.nentioned factors, as well r the role of these factors by Uhemselves, in susceptibility to cancer ara currently being atudied. Kouri, R. P. and Nebert, D. W. (/llkro6lolog/caf Aisoclates, Inc.) lo: Hiatt, 11. Ii., Wataon, I. D. and Winsten, 1. A. (eds.)' OrlSfiar o/ Hrrnan Cancer: Book B Mrchanlinu o/ CanclnoRenefi,r, Cold Spring Harbor Confer- ences on Cell Prdiferation, Cold Spring Harbor, N. Y.: Cold Spring Harbor Laboratory, 1977, vol. 1, pp. ta 11-fi13. Other arpportr National Cancer Institute. , Pnom the Dep.rtment of Biochemical Oncolopy, MkrobiobRkiql Arociates, Ine., aod the Developmental Phartnacolory Branth, National Institule of Child Health and Human Ikvelopment, Bethesda, Md. 2,),7,fi-TETRACHIARODIBPNZO-r-DIOXIN AS COCARCINOOEN CAUSINO )-MPTHYId'HOLANTIIRPNGINIT7ATP.D SUt1CUTANEAUS TUMORS IN MICE OENEI'ICALLY `NON-RESPONSIVE' AT AH LOCUS There it growing evidence that a prereaui.ile for mutaReania and earcinorneais by many. it not aB, polycyclie hydrocarbona is metabolism to neactive intermediates by rytochrome P-4S0-soedialed rrronooaygenaw wrch as aryl hydrocarbon hydroaylaae (AHH). 2,7,7,8-tetrachlorodibenzo-pdbain (TCDD); which is a potent Inducer of AHH activity and Pr4SO in both responaiw and nonrespomive mtoe, was us.d In this study to daterruina whether it aould enhance Ihe .uaceptibility rot C37BL/6 (responsive) and DBA/2 (nonrtaponsive) mice to 3-methykholanlhrene (MCA)'induced can- cers. Eaperimenlally, the possible effect of TCDD on four hepatic enzyme acdvilies. AHH, epoaide hydrae, Rluuthione S-traesferase, and uridine di- phosphate-Rlucuronoayltransferue, were studied. la the liver of either Nrain of mice, 12 to It hours after a high dose of TCDD, the magnitude of In- erease in Allli was many times greater than any change in any of the other enzyme systems. At an i.p. dose that killed 30 to 70% of the animals in sach group of DBA/2 or C37B1/6 mice, TCDD e.wed no lumors in the sur- vivors 36 weeks later. TCDD given I.p. to C3781J6 mice two days prior to, or simuUaneously with, s.c. MCA did no1 dfeet the MCA carcinogenic Indes, while i.p. TCDD Riven b DBA/2 mioe two daya prior /o s.e. MCA incrcased 'N slightly. When s.e. TCDD and s.c. MCA were given sfewllaoeoualy in the same vehicle to DBA/2 mice, Ihe carcinogenic Index Increased markedly. These results Indkate that TCDD is not earcinoRenk in this lest system. However, k docs appear to be a eocarcinoten that might act by indudng AHII activity and its associated P,-4S0 at the ake of inoculation of MCA in genetically noruaponsive mice, thereby resultinR in more eflkient metabolic conversion of MCA to the prosimN or ullimate carcinogen. Kouri, R. E. ef..f. (MkroAtolotkat Assoclater, lne.) Cancer Rtsercil )t<:2777-27ta), 1978. Prom the Deparlment of Biochemical (McoloQr, Mkrolrloloolicsl:Associate., Inc.; the l.abora/ory of ('htmnlry. National Institute of I,rrhtiris. Mclabarlism, and Digestive IHseases; and the Developmental Pharmacology Branch, Na- tional Institute of (:'hiW Ilealth and Human Ikvelopment, Betheda, Md. 22 23

1 COMPARISON OF THP EFFECTS OP BEESWAX:T7t1OCTANOIN AND T RIOCTANOIN VEHICLES ON 3-METHYLCHOLAN INRENE, BI:NZOIaJPYRENE, AND 7,12-DIMETf1YLBENZ(aIANTIIRACENE SUBCt1TANEOUS CAR('INOOENE.SIS IN TIIREE STRAINS OF MICE AND ONE HYBRID In carcinogenesis studies, aolubilization of a suspension introduced into warm becswas to form test implants tor asisnal models determines both the dose that can be administered and the doss available to the individual tarilN cells at any point. The present experiment attempts to determine the relative carcinogenic effecu of three diHerent aubeutaneous doses of 3-mahylcholan- threne (MCA), benzo(alpyrene (BP), and 7,12dimethylbenz(alanthracene (DMBA) suspended in Iriuclanoin, as compared 1o a 1:1 beeswaa (B): Irioctanoin (T) vehicle. Three inbred snd one hybrid mouse atraina were used in order to determine if tunar induction was relaled to a ei/ference in 1he ability of the straina to solubilize and metabolize material from the pellet compared to their ability to metabolize the qrcinogens when sdministered In a soluble form in Irioctanoita. Median tunwr doae kvels were ai6nifksntty higher when the three earcinogem were suspended in trioc/nwin. With B:T, the three carcinogens differed in their abilities to be absorbed or solubilized from the vehicle by the various strains. Is C3H/Aat mice, BP in B:T failed to produce tumon; so did MCA. BP, .nd DMBA with II:T in BC3F, mice. Neither were any tumon induced in the C37BL/6 tlralo by DMBA or MCA la B:T, or in DBA/2 animals by BP or MCA in B:T. These data iadicate that the interpretation of lumor induction results obtained with B:T vehicle may be related to the conditiorn of bioassay rather than to the earcinoger.ic potential of a compound Whitmire, C. E. and Lopez. A. (M(croblologkat Asrociarei, Inc.) Jor.nd o/ dhe Narlonal Cancer /nstirrre 61(1) :1107-I 111, 1978. From the Department of Experimental OneoloBy, Microbiological Associates. Ine., Bethesda, Md. INDUCTION OF TYPE C RNA VIRUS FROM CULTURED RABBIT LYMPIIOSARCOMA CELLS Type C RNA viruses have been Implicated in the etiolop of lympho- hematopoietie tumors. Consequenlly, there have been extensive attempts to kwhte infedioua type C viruaes from species in which these neoplasma occur. Recently, type C viral Information (p30 and RNA-directed DNA polymeras. /RDDP/), but not complete infectious virus, was demanstrated in W11/1 rabbit spontaneous lymphosarcornaa. The data presenled here ahow that hak+itenated pyrimidine (S'-iodo-2'-deosyurine. or IdUrd) induces the release of type C RNA virus partick(s) containing an RDDP and the p39 structural prolein, which, although they appear to posaen unique snligenic delerminants, share sonx in common with other type C virvses. Hybridizdion between rabbit virus DNA and DNA estracled from normal rabbit liver revealed cellular DNA wrnh ntnletthJe sryuentcs h..mulugtan lo Ilwtse rd all laheled cnmplcmentary I/N 1 U.u.. nIN .•/ the t.bl.,t vir.l t.n..mc 11w+. twNh mtrm.l rahhd liver I)N 1•rn.l 11N1 I...u. uh.nr. ..mlun nu. kuhdc sryucut cf related I to the rabbit virur, indicalin8 that the lalter is truly endoperww and not a contaminant. To prove that this Is Mdeed w, the virus muat now be isolated, characterized and compared with othtr type C viruses as well u with cellular DNAs. To this end, a cell N.e which will allow for the replication of tlr induced virus is being sought. Bedittian, H. U., Foa, R. R. and Afeier, N. Jorrnaf ol Ylroloty 27(2):313-319, 1978. Other support: U. S. Public Health Service. From The Jackson l.aboralory, Bar Harbor, Me. TRACIIPABRONCIIIAI. CYTOLOOIC CHANOPS IN MAI.IONANr MELANOMA Hisliorytes counted in smean made from the tracheobronchial waahiap of 208 patients with maliinant melanomas were found to be ).12 times more rlwmerou. 11un those in a control group matched by ses. age (decades) and smokal8 habit butt without any type of prediaBnosed malignant lesion. Since 52 of the patienu with melananas had been followed up for period. up to 40 eantlu after surfiery, a further attempt was made to coaelats tha mortstily with the number of bisllorytes found in smears during operations. Of these 52 patieet., 40 were still alive. Among the 12 patients who had died. d had histiocyle coww below 649 (the mean number for the mclanorea series) and six above that oount, or a high 1o low count ratio of 30%, whils 30 out of the 40 patieeb who bad survived Md high hisliocyte counu, or a high to low ratio of 75%. The difierenoe in ratios belw«n the two aeeties was of borderline statistical signiBc.ace. The large percentage of high tracheo- bronchial bistiocyte oounb in the survivor group probably indicates a atroq immune cellular respoene, which may explain the Nth survival nte. Tbers fore, since morlalNy depends on a variety of facton, these findinp sn presented simply as a method of asus.in8 boat response in malignant diuw. C)haton. 1. aI. aJ. Archives o/ Pathology asd Laboratory Medlci.e 102:631-631, 1978. Prom the Department of Aneslhesiolop, New York Univessity Medical Cenler, New York. DIAONO.4TIC AND PROONOSTIC. SIONIFICANCE OF TRA('HI?OBRON('HIAI. EPI111P.1_IAI. MULTINUCLNAT7ON hor this cylololai study, traobronchid washin were obtained from /,910 eonsenlin~ patienlsic of bolh sesesiheabout to under~op~encral endolracheat anesthesia for surgery. One half of the total group had malignant disease and the other half, matched by sea, age (decades) and smoking habUa but with- out malignancies, served as eontrola. Besulls showed that the mean percentage of mullinuckaled cells (pmnc) in smesn from patients wilh malUgnancles and from all controls was 2 381007 and 1.42.tO07 respectivelT (P<0(NI0S). In cases were sui><lass/fied by age or sea, the ddlererke in hmnc hctwccn 2 3

BACTI?RIA1. CLF.ARANCE FROM T11E LOWER RESPIRATORY TRACT OP 7 FIL' MOUSE: EFFECTS OF ACUTE CIOARETfE SMOKE EX POSUR E Existing evidence suggests that the mucoeiliary and alveolar mscrophaje systems play  central role in hoet defense against inhaled inanimale and infectious agents. "Ihis study was undertaken to examine the eRecto of acute esposure to puffed cigarette smoke on bdt resistance to an airborne bac- terial challenge, and to assess the revctsibility of smoke-associated changes in bacterial ckarsnce. For this purpoae, simultwseorn measurements were Iaken of the numhen of viabk bacteria remaininR in the trachea and lungs of mice at various intervals after the inspiration of aerosolized Sraobylococcrs arrers In the sbsence of cigarette smoke (control group), during smoke inhalalion, and after the cesaation of smoke exposure. Rapid clearance of S. arreur from the trachea was seen after bacterial implanlatioe by an aerosol exposure sys- tem: 35% were cleared in 13 min. Sf% in 30 min. 73% in I hr. e4% in 2 hrs, and 95% in 4 hn. l.un6 ekaranw was equally eReclive, but not as rapNl: )17f% of the organisms were cleared in 13 min. 42% in 30 min. SS% in I hr. 70% in 2 hn, and 90% in 4 hn. When smoke was inhalcd, the following effects were noted on the mice: within IS min. after bacterial chal- kn`e, snwke<zpoud mice cleared 74% of the bacleria from the trachea, and control mice showed )4% clearance with a relative retention ratio of 2.5. TAis ratio was maintained with minor variation over the entire 4 hour smoke- exposure period. In contrast, esposure to cigarette smoke was accompanied by an impairrnent of lung clearance and agraded increase in bacterial reten- lioo related to the length of time the animals were exposed to smoke. Re- venibility studies, however, showed that bacterial counts from both the trachea and lunp of mice eaposed to cigarette smoke for I hr returned to the levels observed in control mice within ) hrs after the lermination of smuke exposure. These findings indicate that cigarette smoke caused a transitory acceleration of tracheal clearance and suppression of lung clearance. Craineri, l. l. In: Developments in lndustrid Mkrobblo:y, Washinston, D.C.. American Institute of Biological Sciences, 1978. vol. 19, pp. 415-426. From the Department of Pathology. Queens Hospital Center, lanb Island )ewish-Hiliside Medical Center AfRliatias, Jamaica. N. Y. POSSIBt.H MF.C)IANISMS OF P.MPIIYSP.MA IN SMOKERS. IN VITRO SUPPRF.SSION OF SERUM PLASTASN-INIIIBIt'ORY ('APACII Y BY FRI?SN ('1OARE'TIP. SMOKE ANl) 113 PREVP.NI ION BY AN7IUXIDAN IS Several recent studies suggest that emphysema in smoken may be due in part to local suppression of elastase inhibition by cigarette smoke. Now, ekctrophnresis and immunaelectrophoresis sMrw that bwNh serum clastase- Inhihitory capacity and Ipha, proleinase Inhibitor /e,Pr)/cla.rase cnmples furruatian are dccrcased by huffered, /resh cigarette snsoke intaK/,rced into aqucnus serum s-rtuiions to whrch pAncreatic elastase is then added. At the same time, the frm, active prole..e content Is increased. Introduclioe of phenolic antiosidants, particularly thymol and hydroquinone, into freshly pra- pared aqueous smoke solutions )tW before the addition of aerurn completely blocks the subsequent auppressas of serum dastase-inhibilory capacity by cigarette smoke. When the effect of substituting nsodel ostidanta for cigarette ,moke in the esperimental system was eaamined in order to further test 1he hypothesis that suppression of serum el.atase-inhibitory capacity by cigarette smoke is due to oxidation reactiorr, all three agenta used (N<hbroauccieL mide, chloramine-T, and hydrogen peroxide) reproduood the suppression of serum elastaae-inhibitory capacity observed with the soluble urwke eompa nents. These results suggest th.t this in vitro inhibitory activity may be du. to smoke-induced osidation of cysteine and/or methionine reaidues io .,Pi. Such suppression of elas/se inhibition by a,Pi In the hmb, whether caused by inhaled cigarette smoke or by environmental oaidants, could be responsible for the proteolylk dcsruc/ion of lung tissue observed In emphysema. Carp. N. and /awv0, A. American Rerkw of Reiolrarory Diieases 11/(7):617-621, 1978, OtAer supports National Heart, Lung and Blood Institute. From the Department of Patholop, State Univenity of New York at Stoay Brook, Stony Brook. (.PS FON('TIONS MftABOI.IQUPS DU POUMON. IV. PROTE.'INASPB ET ANTIPROTCINASI±S EN PATHOLOOIE PULMONAIRE This review presents the body of evidence supporting three porsble \y- paheses concerning the development of hurnas pulmonary emphysema, a.d formulales several questions that must be answered in order to perfect more sophisticated eaperimentd models which will ehscidate its patho6ene.is. The most popular hypothesis cotniden emphysema to be the result of a disrupted homeostalic equilibrium between pulmonary proteasea and antiproaeases, based on the following observations: (1) isscreaed proteinase activity in the luo6 results in emphysema; (2) endogenous enzymts can induce emphyserssatour like lesions; (l) there is a correlation between the proteinase-antiproleinasa equilibrium and the clinical evolWion of the disease; (4) pulmonary neutro phils and macrophages are activated in auch a manner that the incre.se In their number is associated with the appearance of emphysema in certain sryF tems. A second hypothesis .utilResta that an ini/i.1 prokolylic (elaNolylic) event unmasks a specific alveolar antigen which triggers a deslrucUve ins- mumrbgic response on the part of the host. Thtee major arguments favor Ihio particular concept: (1) once trillitered. Ihe alveolar destruction continue. I. the absence of any deteclahle elaslase; (2) immursologie mediators iuduce the rekase of various enzymea, including elas/se; (3) emphysema patients have elevated concentrations of circulating anticollagen antibodies. The third hypo• thesis suggests that either ezposure to environmental faclon, such as tobacco arssoke, or physiologic aging mechanisms kads to degenerative proctsaes ler. minsting in en,physema. Sunh rkgenerauon could result from ae acquired wseeplihdity of elatin to degradation, from increased neutrophilic degranu- Ialioa, or from a greater af6nily of the enzyme for its substrate. Navorinb this 28 29

last hypothesis are the facts that: (1) environmental fsclon can inlluence the degradation rate of connective tissue; (2) anUproleinasew, proteinases and the rekase of enzymes are influenced by physiologic aging as well as by environ- menld lacton responsible for the development of emphysema. Unfortunately, none of the esisting models utilizes completely homologous ekments, nansely, lunt, enzyme and inhibitors from the same speclea, and none provides a time continuum analogous to the several years required for the evolution of the patholo6ie processes in man. In addiliM the statistically demonstrated rela- tionship In man between empbysema and tobaaeo smoke has not been estab- lished In the available eaperieental ntodeM, and data concerning the relation- ships within the lung between the syolhais, rekaae, and elimination of elas- tase or its inhibitors are still IackieK. Even if the first hypothesis currently seems to best espl^in the pathogenesis of human emphysema, much additional work is needed to clarily the ensyane:lnbibitor equilibrium and the factors likely to modify it. WeinDarm. G. and Kimbel. P. fa Rrrre dr M/dtclnr 1 S()6 ):1509-1 S 11, 1977. Other supports National Heart, Lung and Blood Institute. From the Pulmonary Disease Seetioa, Albert Einstein Medical Center, Phila- delphia. DEGRADATION OF TROhOEI.ASTIN BY PROTEASES F.Iaslin, which is largely responsible for maintaining the elasticity of major blood vesseis and lung tissue, is a highly insoluble protein. However, a single polypcptide, tropoelastin (m. wt. 70,000), appears to be a soluble intermediate in the biosynthesis of the fiber. In studying the pathogenesis of chronic obstructive lung disease (emphysema), eaperimentd models have dem- onstrated a strong correlation between the production of emphysema ^nd the cleavage of soluble elastin. The fact that this process may involve the peri- odic destruction and repair of pulmonary lisaue, moreover, suggests that in- tetruplion of elaslin biosyMhesia by degradatioa of tropoelastin could play a significant role in emphysema development. As a fint step in eapbrinR this possibility, the present report describes a simple asaay capabk of detecting a single break in the Iropoelastin polypeptide ehain, and she protein's sensi- tlvily to a number of proteases. Purified radioactively labeled tropoelastin, incubated with dilute solutions of proteasea at physiologic p11 and ionic stren6th, was rapidly de6raded by a variety of these enzyrnn, includin6 kuko- cyte and pancreatic elaslase. This vulnerability of tropoelastin to proteolylic digestion even though both enzyme and substrale are cationic at neutral pll, may be parlly esplained by its probable configuration as a random coil. Be- cause even a single cleavage of the Iropoelastin chain would probably siRniB- candy diminish its ability to lorm normal elastic 8ben, any consideration of the psthogenesis of emphysema should include the potential role of any num- ber of lwptiJasus that might he rckased in the lung. ('hrrstner, P. WnnAam.n, C, Sloan, S; and Roseotdoum, 1. Anu/vnt at Mrarhrmin.r RR 6141 hNR, 1978 OI tiar ar. pport r NRtional Institutes of Heahb. From the Center for Oral Research, Department of Anatomy and Histokgy. School of Dental Medicine, University of Peorrylvania, and the Pulmonary Disease Section, Albert Einstein Medical Center. Philadelphia. PURIFICATION AND CHARACTERIZATION OP CANINE a-l-ANTIPROTEINASE During a course of studies on the etiology of eaperimental canine em physema, it became necaaary to purify canine rl-antiproleinaaa (AP) to serve as an antilieaJc and biochemical standard for diAerentialion of the vari- ow paMease inhibilors found in The dog lung. The present methodology pap,r describes the purilkation of dog AP 94fold with a 25% overall yield. The purification scheme includes anionsaehan6e ehromatography, to separate away the bulk of the serum albumin; allinity chromatography by insolubilized con- canavalin A. to remove most of the other serum proteins as well as traces of albumin; and, enatly, sizing on Sephacryl-S-200. Unique to this puriika- tioe scheme is the batch use of insolubilized hemoillobin-SepMrose beads to remove the ubiquitoua contaminant haptoglobin. Characteristica of the dog AP are the presence of at least two iaoinhibitor forms and its lack of immu- nok+gicat crosa-reaetivily with Munau AP. Abrams, W. R.. Kimbel, P. and WdwDarrn, G. Alocliemlitry 17(17):3336-3361, 1978. O/Aer wpporNr National Institulea of Health. From the Department of Medicine. Pulmonary Disease Section, Albert Eia sleia Medical Center. Philadelphia. SPECIFIC LYSINE I.AHELINO BY tsOH- DURING AI.KAI.INE CLEAVAGE OP TIIE orl-ANTITRYPSIN-711RYPSIN COMPLEX Scrine proteatN:s cleave proteiua by binding to the amino acid for wMeA they are specific and forming a series of intermediales, includinp a ktrahodral adduct, an acyl ester, and two frapmenu of The protein and the free enryerr. 11 has recenlly been suggested that the or1-anlitryprin-trypsin eomples is an acyl ester analogous to the acyl inlermediate that forms helweeq Irypsin and its substrates. This cornpka can bd split at a high pll, releasing a component of . 1-antilrypsin, which has a new earbosy-terminal lysine and is missing a peplide of about 4000 daltons. In order to determine whether the I-anti- trypsin Is bound to trypsin through this new carboay-terminal lysine, as ea- pected it the slxsve hypothesis is correct, the eomples was split In the pres- ence of 18111 . When the csrbosy terminal lysinc thus obtained was cleaved with earbosy-peplidase B. singly labcled, doubly labekd, and unlabeled lysine were recovered. '11hese data support the hypolhcsis that the ~1-anlitrypsin- 31 30

trypsin complex Is either an acyl ester or a tetrahedral precursor thnt is traru- formod into the acyl ester form at a high p11. The methods use4 in these determinatiom may prove useful in establishing which a-l-antitry fsin amino acids bind covaiently to each enzyme, in the event that other enrymes are bound by a similar mechanism. Cohen. A. Q. er .l. procrrdlntr o/ the NaNonal Academy oJ Sciences o/ the United Stotes oJ Amtrka 74(10):4311-4314, 1977. Other supportr National lieut, Lund and Blood Institute. Prom the Department of Mediciee, Temple Ueivenity Hesdth Scir nces Cen- 1er. Philadelphia; and the Department of Pharmaceutical Chemistry, School of Pharm.cy. University of Cslifornia, San Pranciaeo. IiYiP.RA(T1ON OF HUMAN Q-1-ANTITRYPSIN WT'ifl PORCINE TRYPSIN The mechanism of the interaction of human rt-antitrypsin with porcine trypsin wss examined by analysis of their reaction producls. The eRects of different molar ratins of s-l-aolitryp.io to trypsin and varying incubation times were analyzed by polyacrylamide gel ekctrophoresia. Results showed that the complct was only slightly degraded up to 24 hrs of continued in- cubation at 37'C, but degradation of the complex became more evident alter 72 hn. One catalytically active component of porcine trypsin was not In- hibited by .-1-snlarypsin 77+is component, which could account for the de- layed degradation of the compks, may be an autolytic product of the trypsin. The amino acid composition of the complex was In accord with that pre- dicted foe a 1:1 molar ratio of enzyme to inhibitor. In addirion, the compk: bore the amino-terminal residues observed for trypsin and native a-l-anti- Irypsin. The enzyme-inhibitor eompkx could be dissociated in alkaline solu- lions, with the release uf a small peptide and a large fragmenl of e-I •anti- trypsin, which had an amino-terminal threosiee residue and a molecular weight between 46,000 and 30,000. These and other findings support the hypothesis that trypsin reacts with rl-anthrypsin at • Lys-Thr bond and that no pcptides of the reactants have been lost from the inlact complex. Avail- able evidence suggests that the .-I-antilrypsin-Irypsin complex is analogous to the tetrahedral or acyl intermediates which form only transiently between trypsio and ils wbtlrates. Cohen. A. d., Otcty. D. and )ames, 11. L e/acAcmlrtry 17( 3): 392-100, 1972. Other supportr National Heart, I.ung and Blood Institute and the (3eneral Research Support Fund of the Temple University School of Medicine. Proen the hrpartnKnt of MedKrne. Temple l/niversity fle.lth Science, ('en ttt, Phd../c1pMa, (scparu.Knt of Mcdnrne, San Frarwuco (icncr.l Ituspital, arwl Pulrm.nsry Clrr ulreed t cnter al Retrarch and ('ardiovasetdar Research Inslbtule• lhnvcrvty .d ('dduro.s, San I rsnci.co I INACTIVATION OF IIUMAN a, PROTEINASQ INIIIBfiOR BY TH1O1. PROTE?INASES Human plasma s, proteinase inhibitor, alw known as .,-antitrypsin. Y the body's principal modulator of serine proteinsea (such as those released from phagocytic cells). This paper reports a careful study of the Inleraction of the two thiol proteinases, pap.ia and cathepsin B1, with a, proteinaae In- hibitor. Results showed that papain dused a rapid decrease in 1he activity of ., proteinale inhibitor. Examination of samples of the incubation mixture showed a shift in the molecular weight of the inhibitor from 13,000 td 47,000, indicating peptide-bond ciewage during the incubation without the formation of a stable complex. Apin, when cathepsin BI was incubated with a, pro- tinae inhibitor, the activity of ths Inhibitor was lod. However, the reaction was signiflcantly different in Ihat the interaction, cleavage of peptide bond(s), and inactivation of the Inhibitor were sloichiometrk. These resulu su4pat a new pathway by which active-inhibitor eo.eentratioos in tisaues may be sub- stantially decreased so that endogenous proteolysia may occur. That is, any type of reactioa which might activate thiol proteinasn could result in the inactivation of normally protective proteinse inhibitors. lohnsoe. D. and Travis. J. TAe eioc/irmJcd Journal 163 ( 3):639-641, 1977. Otber supports National Institutes of Health. From the Department of Biochemistry, The University of Oeorgia. Atherr; and the Tissue Physiology Deparlment, Strangeways Research Laboratory, Cambridge, England. METABOI.IC ACTIVITY OF DBVELOPINO RABBIT 1-UNO The uptake and metabolism of 10111 kuciue, (U-'4C) glucose and 1'11) palrnitate were studied in late fNal, aewbwo, and developing rabbits ,aid ootsr pared to that of adult and old (1-1.5 yean) animals. Although lue6 com- position did not change markedly, lung metabolism showed dreat diAereooa at various developmental periods. Ltucine iocorporation inlo protein was highest in fetal and neonatal luap, and decreased 30% during /ho flrst week after birth. Patmitic acid itecorporatiou decreased during the 1lrri week at/er birth from 150 nmo// 100 mg/hr to tS nrnoV 100 mg/hr at 7 days of age: it increased thereafter to 170 nmol/ 100 mg/hr at 4 weeks of age and re- maioed at that level throughout the entire period studied. Glucose uptake and lactate production were highest io fetal lunp; fatty acid synthesis from glucose was alw highest at this age. 7bese observations show that late fetal lung has a high metabolic activity that oorrespoods to the high synthetic do- awnds of a rapidly growing and di/ftrestiatiod orpa. N.mo.h, M., Sbechter, Y. and Iluooab. P. Pediatric Research 12:93-100, 197fa. O/Arr .upp.rtr National Institutes of Healtb. From the Deputment of Physiology and Biophyaica, Georgetown University Medical School, Washingtoo,1) C. 33 12

r t I.IpOPROTF.IN LIPASE ACT7VITY AND BLOOD TRIGLYCERIDE LEVELS IN FETAL AND NEWBORN RATS Lipoprokie lipue u known to play a role lo clearing circulating W- slyceride, but it may aks.o have a special fusction In Ihe growth and matura- tioo of individual organs. To Investigate this, /ipoproteio lipse activity in lung and beart was studied in fetal (17-22 days of gestation) and newborn (day of birth until 30 days of age) rala. Blood triglyceride kveb were measured at all ages beginning at 17 days bo rle% and eaayme activity in epididymal, omenlal, and parametrial adipose titrua wr tested after 1!8 days of age. The developmental pattern of lipoprokis lipass diQered markedly in fung and heart. I.ipoprotein lipue activity wsr abeM In Ihe heart until Ilve hours be- fore birth; it increased gradually after birtL from 7.9% of adult activity to 17% at three days, 59% at eight days, and 73% at IS days. 1lr: activity dropped sharply from 75 to 49% of adult activity at weaning (day 21), and adult levels were reached at 24 days. 1s Ihe lung, eoatrasted to the heart, lipoprotein lipase activity wr high is the fetus (R4% of adult acti-ity), de- creased immediately sfter birth to 45% of adult activity at two days, aod remained at that level up b 11 days after birth. Enzyme aetivity rtarted to rise again at IS days and reached .duN levels at 21 days of age. Adipose tis- sue was present in trace amounts before tk+e age of two weeks. This qudy, which shows that lipoproteio lipase activity ia high in fetal lung d•iring the period of marked surfactant synthesis, suggests that circulating triulyceride- fally acids are used by the fetal lung for surfact.at synthesis. Naneouli. M. er at. ledlank Research 12:1112-11 J6, 19711. Other alpportt National Institute of Health. From the Department of Physiolop aod Biophysiu. Georgetown llnivenliy Medical School, Washington, D.C. QUANTI TATIVE CIIARACTERISflCS OF THE PEYRTER (APUD) CELIS OF TIIE NEONATAL RABBIT LUNG IN NORMOXIA AND CHRONIC HYPOXIA In this study of the quantitative characteristics of Feyrter or amino-pre- cursor-uplake-decarbosylalion (APUD) celb, counts were made of the APUD cells of 1-. S-, and 10day-old white New Zealand rabbits in normosic and chronic hypoaie states. A li6ht microscopy survey for nerve fibers in the epithelium was also carried out. Results showed that the ulls, both singly and in groups, were present in the epithelium of sd1 the intrapulmonary airways, although they were more frequeotly seen in the small bronchi and respiratory bronchioks. The number of Feyrier cells declined from one to 10 days of age (n normosie rabbits, whereas in the eaperimenul group (chronic hyposic ), the number of cells was low at one day of aee and no signifkanl changes occurred during the subsequent nine days. There was some indication of de- granuFslNiis of cells in the hyix+sic group It is ppnsibk that environmenlal snd/ar phyruilutarl factors asuxuted with the start of etlrautetine life, or 34 I lung devebpment,emay affett the apparent oumber aod probable level of aa tivity of these celb. These changes seemed 1o be enhanced by hypoaia, as observation which suggests again Uut these cells could poribly represent stor- age sites for 3-hydrosytryptsmioe. In this sludy, alw, intr.epithelial nerve flbcn in bronchi and bronchioks were found but they were -sol hmited to inner.ations of Feyrter cells or related eell bodies. Ilern.odez-Vasquez, A., W/d, l. A. and Quay; W. B. Thorax 32:449416, 1977. Other supports College of Agricultural and I3fe Scieooa, University of Wiscoasin, Madiaoa. From the Lkpartment of Veterinary Scknce, aod Neuroendocrine Soctb., Waismao ('entcr on Mental Retardation and Human Uevelopmeot, University of Wisconsio, Madison. A RADIOAU'TOORAPHIC STUDY OF THE NEUROEPITNELIAI. BODIES OF THE LUNGS IN FETAL AND NEONATAL RABBITS In a group of while New England rabbiu, 29-day-old fetuaes wer. I.- 1ed wbcutanewrly iw rfero with tritialed thymidine and the does were killed with sodium peatobazbNal injoetion, so as to obtain 2 fetuses for each o. the following stages: 2, 4. 6, !, 10, 12, 14, 16, 20, and 24 hn efler ail- thymidine injection. In a seoond group, I-day-old rabbita of the same breed as the fetuw, were also injected subcutaneously with sH-Ihymidine, and aacri/ked at 2, 4, 6, la, 10, 12, 14, 16. 16, 20, 22 aed 24 hn after injecton. Multiple samples Iaken from all lobes of Ihe lun6 were processed for p.raaln sectioning and radioauto6rarns were ezamined to establish whether the neuro- epi/helial bodies (NEBs) were undcrlioing mitosis and if so, to eaamine pos- sible variations in mitoMc rates and labeling indicea al the two different a/aloea studied. Results showed that thero was no uptake of Iritiated thymidine by 1he Nt!Bs and no mitotic fltura were found there at any of Ihe stages aludied. Also, the NEBa were not derived at this lime lrom prdiferations of other kinds of epithelial celb in the intrapultnonary, airways. These results stroatly suggest that the difference in numbers of NEBs previously observed by these authon, between the 29-day-old fetus and the I-day-old rabbit, is due either to regranulalion or acquisition of argyrophilie material by the NEBs or to diflerentiation of other epithelial lypes. It is eoncluded that Ihe NI?Bs am composed of welldilferentiated cells, which have a reduced capacity to un- derooo mitosis, during Ihe neonatal period. Hernandez-Vasquez, A., Wlll, l. .t, and Quay. W. B. Celi and Tissue Research 186:207-207, 1978. Ot6er support: College of Agricultural and Life Scienees, Univenity of Wisconsin, Madison. From the 1)epartment of Veterinary Science and Neurexndocrina Soction, Waisman ('cnter on Mental Retardation and Human Ikvelopment, l)nivenity of Wuconsrn, Madison. 35

I i i I fSi i i .~.~. I t9OM8ESIN-L1Kt31MMUNORt3ACT1V17Y IN TNB LUNG In this e:perimental study of the eadocrioe aspects of the lun6, human fetal and oeooatal hmp, ranging In age troeo eight weeka of gestation to tour osontha poanatal, were obtained froar 25 male and femrde wbjecta. Samples of tissue were taken from adjacent Inner, middle aod outer regions of each lung for Immunocytocbembtry (IC) and radioimmunoaaay (RIA), and aotisera directed to the C-tenaioal portion of amphibian bombesin and two bombesio analogues were raised io rabMb is several different ways. The optimal antiaerum for RIA waa foasd b be that lo pute amphibian bombesio and to the /Lys'ibornbeain aoalogte, w<tiereas for IC it was antiserum to the mr'ibombeaio analogue. Results •bowed cells with bombesin-like Immuno- reactivity nuiny in the bronchial and bronchiotar epithelium of fetal and neon•Ial lun6, both as single oel4 and aa kroup.. This immunoreactlvit7 was found by RIA to range from 2 to 43 ptnol per gm wet weight of ti•sue, whereas in preliminary atudies on human adult lung tso atls containing bombtain-like immunoreactivity were detected. This age-dependent d'astribMNion of cells containing bombesin-like Immunoreactivity, ssuggests that these eells may be of signiAcance during development and birth. tlombesio itself is one of a growing group of pepfidea found to be common to brain and Cut that seem to act both as neurotrammitten and aa local or ayslemie tarmooes. While the role of bombesin in the lung i• atitl specula/ive, it is imporunt Ihat, 40 years •lter Peyrter postulated an endocrine role for the lung, an endocrine peptide bas been found in the APUD cells of human fetal and ucoaatal lung. VYharton, l. er .l. ( W itl,1. A. ) Nature 273:769-770, 197t1. OtAer aappo rtr Medical Research Council, Cancer Research Campaign, and Stiftung VolkawaIcnwerk. Prom the Departments of HiNochesnitdrp and Medicine, Royal Poettraduate Medical Schtwl, Hammer.mith Hospital, Laodoa, Eagl•nd. IS i71E LUNG A PARA-ENDOCRINE ORGAN? lo addition to gas eschange, the lunp conduct activities that are sini- lar so those of endocrine glands. TAeir uo'tqtse ultraatrueture and pssitioo In the cireulator7 system enable Ihem to process certain hormones and pro- hormones (l.r.. Neraids, biogenie amine., proMaglandins, polypeptide hor- rnooes, and adenine nuckotidn). Conseqiuently, they probably Influence ape- ciAc actions of distant /issues and otgans, although they actually ryntheaise and release only prosta{landin related substances. While the intact lungs ae- ketively prooess only specific analogues within chemical groups of hormonea, this discrimination is lost when their structural integrity Is disrupted, indieat- in6 that in the natural state entymca are so partitioned among different cells and ore•nelka that some have accer to circulating hormones whereas others da mN StKh distlnction it a major determinant of the hotmone: fate and of the ulrsnutr d/.1M1\ItM.n ot the mtt.t..dic pr..fuct. Specifically dncus.ed art the htr. .Intmt d.cn pa...re thn-th the lunp of bradykinm, •(wdtnt htl..t.n..r .h..h ~% i.-t.tlt in..t..urd and of anrn.ttnsin 1. which is tn I activated through Its•conversioo to Ib lower btxnologue angiotenein II, a awat polent hypertensive. 'ibw, the ability of the tvnp to elimioate a 6oraaatr that lowen blood pressure while forming one 1lut raisea it, suggests a possible role in the regulation of blood preanure hoerowtasir. It also appears that a single ensyme, ankiotensio converting enzyme (kiaioaae 11), may aocouot tor both the inactivation of brad7kioio and the eoaversion of aopoleaain. In add/- tbn, it sow seema likely thot the htep uo also form aokioteaain 111, an a/do- aterone secretosogue that Is eveo nsore potent than angioteods H. It may be, however, that this particular mochaaiun in important for twaintaioios wuaioed elevation of •yuemk arterial blood prtnwrre levels only under wsch ciraws- danoes u result from trtatmenl with diuretia or streoutws e:erci.e, abat Y, when she plasma volume Is low or wheo the plasma reaio level i• eatraney high. 11 i• probable Ihat ahe /otal clarificalion of the rok of the htop io ther hoateo.talic mechanisny will be /ound at the cellular and molecular levels. The remainder of this review etamines Ihe variow sludia that have led to the formulation of /hcae concepts and justifiably ends by asking: la the hty a p.ra-eotlocrine organ? Ryan. 1. W. and Ryan. U. S. Tlie Amrrlcan lorrnd o/ 6lrJiclwr 67:S9S-60), 1977. Other wpprtr U. S. Public Health Servioe, Hartford Poundation, Inc. and the Heart Association of Pahn Seach County, Fla. From the t)epartment of Medicine, The New York Hoepitdl'ornell Medical Center, New York; the Papanicolaou Cancer Research lu.litute, and the De- partment of Medicine. University of Miami School of Medicine, Miami, Fta. ISOLATION AND CULTURE OF PULMONARY ARTERY ENDOTHeL1AL CELLS It is increasingly evident that endothefial oella are rmscb more than a mere mechanical barrier between blood and parenchyma. Since they are known also to diRer struclurally from one vaacular bed to aoother, it haa beeo suggested that they may d'ifer functionally as well. In order to further teat this hypothesis, however, endolhelium smW Aral be obtained from vari- ous aources and grown in pure, welleharackrized culturea. To facilitate such studies, the means of iaolation, culture and characterization of calf pulmonary artery endolhelium are detailed in this report. Theae cells may have siriA- eant importanoe in terms of specific metabolic aetiviries since there an inN- eation• that the lunp, and pulmonary endolhelia) cells in partieular, have a major influence on the mechani•m that regulates rhe hormonal composition of systemic arterial blood. Ryan. U. S. rr d. Tisst.a d Cell 10( )): 311-534, 1975. Other arpprtr U. S. Public Health Service and the /ohn A. Hartford ' Foundation From the Ikpartment of Medicine. Univer.ity of Miami School of Medicine. Miami, PIa. 37