TRAF4 deficiency leads to tracheal malformation with resulting alterations in air flow to the lungs.

TRAF4 is one of six identified members of the family of TNFR-associated factors. While the other family members have been found to play important roles in the development and maintenance of a normal immune system, the importance of TRAF4 has remained unclear. To address this issue, we have generated TRAF4-deficient mice. Despite widespread expression of TRAF4 in the developing embryo, as well as in the adult, lack of TRAF4 expression results in a localized, developmental defect of the upper respiratory tract. TRAF4-deficient mice are born with a constricted upper trachea at the site of the tracheal junction with the larynx. This narrowing of the proximal end of the trachea results in respiratory air flow abnormalities and increases rates of pulmonary inflammation. These data demonstrate that TRAF4 is required to regulate the anastomosis of the upper and lower respiratory systems during development.

Induction, maintenance, and reversal of streptozotocin-induced insulin-dependent diabetes mellitus in the juvenile cynomolgus monkey (Macaca fascilularis).

BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) is the second most prevalent chronic illness of children. Investigation of the treatment of IDDM is hindered by the lack of a reproducible and easily maintained non-human primate model of this disorder. METHODS: We induced IDDM in 11 juvenile cynomolgus monkeys after a single (150 mg/kg) intravenous injection of streptozotocin (STZ). All diabetic monkeys were treated with insulin twice daily, based on a sliding scale. Subcutaneous vascular access ports were surgically placed in each monkey to facilitate serial blood sampling and drug administration. Allogeneic pancreatic islet cells from unrelated donors were subsequently transplanted into the mesenteric circulation of all STZ-treated monkeys. RESULTS: Mild, transient nausea and vomiting occurred in all animals after STZ injection; however, no additional signs of toxicity occurred. Within 36 hr, all monkeys required twice daily administration of exogenous insulin to maintain a non-ketotic state. Serum C-peptide levels decreased from >1.2 ng/ml before STZ, to between 0.0 and 0.9 ng/ml after STZ, confirming islet cell destruction. Animals were maintained in an insulin-dependent state for up to 147 days without any observable clinical complications. Subcutaneous vascular access port patency was maintained up to 136 days with a single incidence of local infection. Islet cell transplantation resulted in normoglycemia within 24 hr. Serum C-peptide levels increased (range: 2-8 ng/ml) for 6 - 8 days in immune competent animals, and for 39-98 days after transplant in immunosuppressed monkeys. CONCLUSIONS: IDDM can be consistently induced and safely treated in juvenile cynomolgus monkeys. Chronic vascular access can be maintained with minimal supervision and complications. This model is appropriate for studies investigating potential treatments for IDDM including islet cell transplantation.

Sequence and structural analysis of feline interleukin-5 cDNA.

OBJECTIVE: To clone and characterize the cDNA encoding feline interleukin-5 (IL-5) cDNA and the 170 basepairs (bp) of the 5' flanking region of the feline IL-5 gene. SAMPLE POPULATION: Blood mononuclear cells from a healthy cat. PROCEDURES: Cells were cultured, stimulated for 48 hours with concanavalin A, and harvested for RNA and DNA isolation. Recovered RNA was used in northern blot and reverse transcription-polymerase chain reaction analyses. Resulting cDNA was used for rapid amplification of 3' cDNA ends, dideoxy chain termination sequencing, and primer extension analysis. RESULTS: Full length cDNA was 838 bp, including a 402-bp open reading frame that encoded a precursor protein of 134 amino acids including a putative peptide signal of 19 residues. Homologies of the nucleotide and derived protein sequences between feline and human IL-5 cDNA were 72 and 71%, respectively. There also was homology between the human and predicted feline cytokines at amino acid positions that are critical for IL-5 receptor binding and signal transduction. The 5' flanking region of the feline gene was homologous to corresponding regions of the human (88%) and murine (72%) genes, and included putative transcriptional regulatory elements. CONCLUSIONS AND CLINICAL RELEVANCE: Identification of feline IL-5 cDNA is an important step toward a detailed, fully comprehensive characterization of the mechanisms that may be operative in the pathogenesis of eosinophilic disorders in cats. The striking homology between the human and feline IL-5 genes suggests that cats can be used as animal models for human diseases characterized by eosinophil infiltration of tissues.

Expression and cytogenetic localization of the human SM22 gene (TAGLN).

SM22 is a 22-kDa protein identified variously as SM22, transgelin, WS3-10, or mouse p27. Though its precise function is unknown, it is abundant in smooth muscle and so may contribute to the physiology of this widespread tissue. We found that cosmid 16b6 contains the entire 5.4-kb, five-exon human SM22 gene (HGMW-approved symbol, TAGLN), and we cytogenetically localized the gene to chromosome 11q23.2. Northern analysis of human adult tissues showed that SM22 mRNA is most prevalent in smooth muscle-containing tissues, but is also found at lower levels in heart. The human SM22 promoter contains nuclear factor-binding motifs known to regulate transcription in smooth muscle, and human SM22 promoter-luciferase reporter constructs exhibited high transcriptional activity in A7r5 or primary canine aortic smooth muscle cells, but show little activity in nonmuscle COS7 cells. In addition, human SM22 promoter activity increased by two- to threefold upon serum stimulation of nonmuscle cells.

Neoplastic diseases in ferrets: 574 cases (1968-1997).

OBJECTIVE: To determine incidence of neoplastic disease in ferrets. DESIGN: Retrospective study. ANIMALS: 574 ferrets with neoplastic disease. PROCEDURE: Medical records from the Veterinary Medical Data Base at Purdue University from 1968 to May 1997 were reviewed to identify ferrets with neoplastic disease. Data on tumor type, organ or system affected, sex, age, geographic location of affected ferrets, participating institution, and year of diagnosis were retrieved. RESULTS: 639 tumors of various types were diagnosed in 574 of 4,774 (12%) ferrets in the database. Sixty-one ferrets had multiple tumor types. Primary tumors were found in every system; endocrine (254; 39.7%), hemolymphatic (97; 15.2%), integumentary (83; 12.9%), and digestive (54; 8.4%) systems were most commonly affected. The most common tumor types were pancreatic islet cell (139; 21.7%) and adrenocortical cell (107; 16.7%) tumors and lymphoma (76; 11.9%). Most (94.2%) pancreatic islet cell tumors were functional. Age of affected ferrets ranged from less than 1 month to more than 15 years old. Tumor incidence was highest in ferrets between 4 and 7 years old. A sex predilection was not found, although tumors were found more commonly in spayed females and castrated males than in sexually intact females and males, respectively. Number of tumors diagnosed increased as the number of ferrets examined increased. Neoplastic disease accounted for an increasingly greater percentage of diseases diagnosed in ferrets during the study period. CLINICAL IMPLICATIONS: Ferrets have an incidence and spectrum of neoplastic disease similar to other mammalian species.

CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma.

Complete T-cell activation requires two distinct signals, one delivered via the T-cell receptor, and the second "co-stimulatory" signal through CD28/B7 ligation. Previous studies showed that the blockade of CD28/B7 ligation alters differentiation of Th1/Th2 lymphocyte subsets in vitro and in vivo. The present study was designed to determine the effect of a CD28/B7 antagonist (CTLA4Ig) on Th1/Th2 development in Schistosoma mansoni-sensitized and airway-challenged mice. Treatment of mice with CTLA4Ig beginning 1 wk after sensitization abolished airway responsiveness to intravenous methacholine determined 96 h following antigen challenge. We also found a significant reduction in bronchoalveolar lavage (BAL) eosinophilia, and reduced peribronchial eosinophilic infiltration and mucoid-cell hyperplasia. Furthermore, CTLA4Ig treatment significantly decreased interleukin (IL)-4 and IL-5 content in BAL fluid in vivo, and the production of IL-5 by lung lymphocytes stimulated with soluble egg antigen (SEA) in vitro. In contrast, the content of interferon-gamma in BAL fluid and supernatant from SEA-stimulated lung lymphocytes from CTLA4Ig-treated mice was increased significantly compared with untreated animals. Thus, CTLA4Ig inhibits eosinophilic airway inflammation and airway hyperresponsiveness in S. mansoni-sensitized and airway-challenged mice, most likely due to attenuated secretion of Th2-type cytokines and increased secretion of Th1-type cytokines.

Differential effects of cyclosporine A after acute antigen challenge in sensitized cats in vivo and ex vivo.

1. We determined the effect of cyclosporine A (CsA) treatment on mast cell degranulation and lung resistance (R(L)) in vivo, and tracheal smooth muscle (TSM) contraction ex vivo after antigen challenge in sensitized cats. We also determined the direct effects of addition of CsA to the tissue bath on antigen-induced responses of TSM in vitro. 2. Cats (n=10) were sensitized by i.m. injection of Ascaris suum antigen (AA); 5 cats (CsA+) received CsA twice daily for 2 weeks before acute antigen challenge in doses sufficient to suppress interleukin-2 secretion from feline peripheral blood mononuclear cells ex vivo. 3. Lung resistance increased comparably within 10 min of exposure to AA (P<0.03). Histamine content in bronchoalveolar lavage fluid from both groups increased comparably within 30 min of antigen challenge, from undetectable levels to 542+/-74 pg ml(-1) post AA for CsA+ and from 74+/-19 pg ml(-1) at baseline, to 970+/-180 pg ml(-1) post AA CsA- (P<0.05; P=NS vs CsA+). 4. In excised TSM, active tension elicited by exposure to AA in vitro was 107+/-38% KCl in the CsA+ group vs 144+/-56% KCl in the CsA- group (P=NS). However, contraction of TSM (n=4) harvested from both groups was abolished or greatly diminished after AA challenge when tissues were pre-incubated with 1 microM CsA in vitro (8+/-8% KCl, P<0.05 vs CsA+ and CsA-). This was associated with inhibited release of 5-hydroxytryptamine into the organ bath fluid of tissues treated with CsA in vitro only. 5. We demonstrated that CsA treatment in vivo does not inhibit the early phase asthmatic response or mast cell degranulation following antigen challenge in sensitized cats. Additionally, the effects of CsA on mast cell function ex vivo do not reflect lack of effects of CsA on mast cell function in vivo in this animal model of atopic asthma.

Muscarinic hyperresponsiveness of antigen-sensitized feline airway smooth muscle in vitro.

OBJECTIVE: To determine the effect of in vivo antigen sensitization (Ascaris suum) of cats on tracheal smooth muscle (TSM) and bronchial smooth muscle (BSM) muscarinic reactivity in vitro. ANIMALS: Healthy domestic shorthair cats of either sex. PROCEDURE: Cats were sensitized and were long-term antigen (or sham) challenge exposed for 6 weeks by aerosolization with soluble Ascaris suum. Tracheal and BSM preparations were obtained and stimulated in vitro by electrical field stimulation (EFS), acetylcholine (ACh, a muscarinic agonist), and physostigmine (an AChase inhibitor). Responses were compared with responses of comparable tissues from sham antigen challenge-exposed cats. RESULTS: Tracheal and BSM from sensitized, compared with sham-sensitized (control), cats had greater isometric contraction (expressed as percentage of the response observed for isotonic, 63 mM KCl-elicited contraction [% KCl]) in response to endogenous (EFS) and exogenous muscarinic receptor activation (ACh). Contractions in response to EFS by TSM from control cats were 74% KCl vs 97% KCl for antigen-sensitized TSM (P < 0.04). Muscarinic responses were augmented comparably by in vivo sensitization; TSM from control cats contracted to 190% KCl vs 230% KCl (P < 0.03) for TSM from immune-sensitized cats. Physostigmine augmented responses of all tissues to ACh so that TSM from control (290% KCl) and antigen-sensitized (257% KCl) cats were similar. Responses of BSM from antigen-sensitized cats had similar augmentation of contractile response to EFS and ACh. CONCLUSIONS: Long-term in vivo antigen sensitization increases numbers of muscarinic receptors on airway smooth muscle or decreases the availability or activity of AChase in cats. CLINICAL RELEVANCE: Modulation of muscarinic receptors may be useful for treatment of asthmatic cats with in vivo airway hyperreactivity.

Doppler echocardiographic reference values for healthy rhesus monkeys under ketamine hydrochloride sedation.

Cardiac ultrasound is a noninvasive technique that is commonly used to serially evaluate cardiac structure and function. Recent advances in Doppler-Echocardiography enable the ultrasonographer to perform a sophisticated noninvasive assessment of cardiovascular physiology. The Rhesus monkey is a frequently used non-human primate animal model of human cardiovascular disease because this species closely models human anatomy and physiology. However, while this species is frequently used in cardiovascular research, standardized echocardiographic values generated from large numbers of normal Rhesus are not available. In the present study, we performed cardiac ultrasound imaging on 28 healthy Rhesus monkeys to obtain normal reference values of cardiovascular structure and function in this species. Nomograms were generated from these data by plotting parameters of cardiovascular geometry and function with body weight. These normal reference data were compared to previously reported values obtained from prior studies that used noninvasive, invasive, and morphometric techniques.

Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation.

Ag-specific T cell activation requires a CD28-mediated costimulatory interaction. This observation has suggested novel approaches to suppress donor-specific immunity, including the use of soluble CD28 antagonists, such as CTLA4Ig, which suppresses transplant rejection in small animal models. In this study, CTLA4Ig therapy was examined in a non-human primate model of allogeneic pancreatic islet transplantation. Two of five CTLA4Ig-treated monkeys showed prolonged graft survival, which correlated with donor-specific hyporesponsiveness in vitro. Humoral responses to the transplanted tissue were suppressed in all treated animals. These results suggest that CTLA4Ig is effective in suppressing both humoral and cellular immune responses in a non-human primate model of allogeneic transplantation.

Cyclosporine A inhibits airway reactivity and remodeling after chronic antigen challenge in cats.

We determined the effect of cyclosporine A (CSA) on airway reactivity and remodeling after chronic antigen challenge in Ascaris suum (AA)-sensitized cats. CSA efficacy was demonstrated by inhibition of interleukin-2 (IL-2) production from phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear (PBMN) cells. Twenty-four hours after the first AA exposure, cats not receiving cyclosporine (CsA-) demonstrated airway hyperresponsiveness (AHR) to acetycholine (approximately 1.0 log increase in PD200 versus baseline; p < 0.01), and a 13-fold increase in eosinophils in bronchoalveolar lavage fluid (BALF) (p < 0.01). AHR persisted (approximately 1.5 log increase in PD200 p < 0.001 versus baseline), and BALF eosinophilia was unchanged in CsA-cats 72 h after final AA challenge. The percent of normodense BALF eosinophils also decreased substantially in CsA-cats (p < 0.05). Necropsy specimens from CsA-cats demonstrated: (1) increased smooth-muscle thickness; (2) goblet cell and submucosal gland hypertrophy and hyperplasia; and (3) epithelial erosion with eosinophilic infiltration. There was no significant change in AHR, BALF, eosinophilia, or histology after chronic AA challenge in Csa-treated cats. These data suggest that CsA inhibits products of immune cells necessary for the development of AHR, airway inflammation, and airway wall remodeling caused by immune-sensitization in this model of atopic asthma.

Cyproheptadine-induced attenuation of type-I immediate-hypersensitivity reactions of airway smooth muscle from immune-sensitized cats.

We assessed the effect of serotonergic inhibition by cyproheptadine on the responsiveness of tracheal smooth muscle (TSM) strips and epithelium-intact third-generation bronchial rings from immune-sensitized (Ascaris suum) cats after exposure to antigen. Cats were sensitized by IM administration of antigen and adjuvant twice over a 4-week period. Sensitization was confirmed in vivo by skin testing with antigen and by physiologic airway responses after exposure to nebulized antigen. Tissues were tethered isometrically to force transducers and were actively equilibrated by exposures to KCl-substituted perfusate. Maximal response after exposure to antigen (expressed as percentage of maximal contraction of each tissue to 63 mM KCl (%KCl) was 169 +/- 18% KCl for sensitized TSM and 43 +/- 18% KCl for sensitized TSM pretreated with cyproheptadine (P < 0.001). Similarly, maximal response to antigen was 81 +/- 27% KCl for sensitized bronchial rings, compared with 16 +/- 14% KCl for sensitized bronchial rings pretreated with cyproheptadine (P = 0.05 vs control). Blockade of leukotriene synthesis by 10(-6) to 10(-4) M A-64077, a selective 5-lipoxygenase inhibitor, had no significant effect on peak response for either TSM (193 +/- 13% KCl vs 169 +/- 18% KCl for sensitized untreated TSM) or bronchial rings (79 +/- 20% KCl vs 81 +/- 27% KCl for sensitized untreated bronchial rings). Release of serotonin from airway tissues was confirmed by the presence of serotonin in the perfusate of 8 sensitized TSM preparations after, but not before, antigen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequence and functional characterization of feline interleukin 2.

Since the discovery of its involvement in the pathogenesis of feline immunodeficiency virus infection ("cat AIDS") and feline leukemia virus infection, the role of feline interleukin 2 (IL-2) has been a focus of particular interest. The purpose of this study was to clone feline IL-2 cDNA, as well as synthesize bioactive recombinant feline IL-2. The isolation of cDNA encoding feline IL-2 was carried out using a PCR-based strategy and screening of a feline leukocyte cDNA library. Feline IL-2 consists of 154 amino acids including a putative signal sequence and has 81%, 69%, 60% and 64% identity to human, bovine, murine and rat IL-2, respectively. Feline IL-2 cDNA was expressed in COS-7 cells. The secreted protein has CTLL-4 murine cytotoxic T cell proliferative activity characteristic of authentic IL-2. These data confirm the synthesis of bioactive recombinant feline IL-2.

The nef gene of simian immunodeficiency virus SIVmac1A11.

The role of the simian immunodeficiency virus (SIV) nef gene in viral replication was investigated in several tissue culture systems. SIVmac1A11 is a molecularly cloned virus which replicates in both peripheral blood mononuclear cells (PBMC) and macrophages, although no disease is observed in infected rhesus macaques. In this report, we demonstrate that SIVmac1A11 contains a full open reading frame for nef which specifies a 37-kDa protein. To investigate the effects of nef on viral replication, a 70-bp deletion was introduced into the nef gene of SIVmac1A11. Analysis of infected cell extracts by immunoblotting revealed that both SIVmac1A11 and nef deletion virus SIVmac1A11 delta nef produced the same viral proteins, except that Nef was absent in the mutant virus. The deletion mutation did not affect viral replication in PBMC, in monocyte-derived and alveolar macrophages obtained from rhesus macaques, and in human cell lines HUT-78 and CEMx-174. In addition, SIVmac1A11 and SIVmac1A11 delta nef exhibited similar patterns of cytopathologic changes and ultrastructural appearances in infected cells. SIVmac1A11 and SIVmac1A11 delta nef did not infect human tumor macrophage cell line U937, GCT, THP-1, or HL-60 cells, although virus was produced after these cells were transfected with either wild-type or nef mutant viral DNA. Similar levels of virus were recovered from U937 and THP-1 cells transfected with mutant and parental proviral DNAs. In transient expression assays in a T-cell line and a macrophage line, the nef protein of SIVmac1A11 did not significantly suppress or enhance expression of the chloramphenicol acetyltransferase reporter gene linked to the SIVmac long terminal repeat. Thus, abrogation of nef did not affect several in vitro properties of SIVmac1A11, including patterns of viral infection in rhesus PBMC, rhesus macrophages, or human T-cell lines.

Role of caudal ventrolateral medulla in reflex and central control of airway caliber.

We investigated the role played by the caudal ventrolateral (CVL) medulla in the reflex and central neural control of airway caliber in chloralose-anesthetized dogs. Changes in total lung resistance were evoked by four different stimuli. These changes were compared before and after bilateral injection of either ibotenic acid (75 nl; 100 mM) or cobalt chloride (75 nl; 50 mM) into the CVL medulla. The four stimuli used to change lung resistance were static muscular contraction, electrical stimulation of thin fiber afferents in the sciatic nerve, electrical stimulation of the posterior diencephalon, and hypoxia. The first three stimuli have been shown to decrease total lung resistance, whereas the latter stimulus has been shown to increase resistance. We found that injection of both ibotenic acid, which destroys cell bodies but not fibers of passage, and cobalt, which prevents synaptic transmission, either abolished or greatly attenuated the decrease in total lung resistance evoked by static contraction, by sciatic nerve stimulation, and by posterior diencephalic stimulation. We also found that injection of ibotenic acid and cobalt attenuated the reflex increase in lung resistance evoked by hypoxia. In control experiments, we found that bilateral injection of ibotenic acid into the dorsal medulla had no effect on the changes in total lung resistance evoked by these four stimuli. We conclude that the CVL medulla plays an important role in the reflex and central control of airway caliber.

Cytologic, microbiologic, and biochemical analysis of bronchoalveolar lavage fluid obtained from 24 healthy cats.

Twenty-four healthy cats underwent bronchoscopy and bronchoalveolar lavage to determine the normal cytologic environment of the lower respiratory tract of cats. Initial screening to ensure the health of the study population included complete histories, physical examinations, thoracic radiography, CBC, serologic tests for feline leukemia virus, feline immunodeficiency virus, and occult heartworm, and sugar and Baermann fecal flotation. In 18 cats, protected catheter brush samples of airway secretions from the lavaged lung segment were taken for culture of aerobic and anaerobic bacteria and mycoplasma. Bronchial lavage fluid (5 sequential 10-ml aliquots of normal saline solution) was pooled and filtered with cotton gauze. The unspun sample was used for determination of a total nucleated cell count. Lavage fluid was cytocentrifuged and 500 cells/slide were scored for determination of the cellular differential. Activity of lactate dehydrogenase and concentrations of total protein and IgG within the supernatant were measured, and assays were performed to detect the presence of IgA and IgM. Complete histologic evaluation of the lavaged lung of each of 6 random-source cats was performed after differential cell counting revealed 18% eosinophils within bronchoalveolar lavage fluid recovered from this group. Alveolar macrophages were the predominant cells encountered; however, a quarter of all cells recovered were eosinophils. A significant relationship was not found between the abundance of eosinophils in the lavage fluid, and either isolation of aerobic bacteria, high total nucleated cell counts, total protein concentrations, or activity of lactate dehydrogenase. Histologic evaluation of the lungs of 5 of 6 random-source cats revealed normal lungs in 2 cats, and minimal abnormal change in 3 others. Evaluation of the lungs from 1 random source cat revealed acute, mild eosinophilic bronchiolitis. We conclude that large numbers of eosinophils may be retrieved from the bronchoalveolar lavage fluid of healthy cats.

Activation of neurons in the rostral ventrolateral medulla increases bronchomotor tone in dogs.

Previous work from this laboratory has demonstrated that the chemical activation of cell bodies in the caudal ventrolateral medulla of chloralose-anesthetized dogs decreased bronchomotor tone by withdrawing cholinergic input to airway smooth muscle. In the present study we determined the bronchomotor responses to microinjection of DL-homocysteic acid (100 mM; 25-50 nl) into the rostral ventrolateral (RVL) medulla of chloralose-anesthetized dogs. Total lung resistance was used as a functional index of bronchomotor tone. Microinjection of DL-homocysteic acid into the 20 sites located in the lateral aspect of the RVL medulla increased both total lung resistance [from 6.5 +/- 0.4 to 9.1 +/- 0.8 (SE) cmH2O.l-1.s; P less than 0.05] and mean arterial pressure (from 125 +/- 5 to 148 +/- 8 mmHg; P less than 0.05). Microinjection of this amino acid into nine sites located in the medial aspect of the RVL medulla increased mean arterial pressure (from 130 +/- 6 to 153 +/- 6 mmHg; P less than 0.05) but had no effect on total lung resistance. We confirmed in three sites that the increase in total lung resistance evoked by microinjection of DL-homocysteic acid was accompanied by an increase in tracheal smooth muscle tension. The increase in total lung resistance evoked by DL-homocysteic acid was not affected by beta-adrenergic blockade but was abolished by muscarinic blockade.

Ischemia potentiates the reflex bronchodilation evoked by static muscular contraction in dogs.

In eleven anesthetized dogs, we found that static contraction of hindlimb muscles that were freely perfused decreased total lung resistance by 0.7 +/- 0.1 cm H2O.L-1.sec, whereas static contraction of the same muscles rendered ischemic decreased total lung resistance by 1.5 +/- 0.4 cm H2O.L-1.sec (P less than 0.025). In ten other dogs, we found that static contraction of freely perfused hindlimb muscles decreased total lung resistance by 0.9 +/- 0.2 cm H2O.L-1.sec, whereas dynamic contraction of the same freely perfused muscles decreased total lung resistance by 1.1 +/- 0.3 cm H2O.L-1.sec. The difference in the magnitudes of the bronchodilator responses to the two modes of contraction was not significant (P greater than 0.05). We conclude that a mismatch between blood supply and demand in working skeletal muscle increases the reflex bronchodilator response to static contraction. We also conclude that dynamic contraction evokes a reflex bronchodilation equivalent to that evoked by static contraction provided that the tension produced by the two modes of contraction are equal.

Canine chronic bronchitis. A pathophysiologic evaluation of 18 cases.

Eighteen dogs with chronic bronchitis were studied using physiologic, radiologic, microbiologic, and pathologic techniques. Twelve of these dogs were evaluated before and after two weeks of oral bronchodilator administration. Thoracic radiographs, tidal breathing flow-volume loops, radioaerosol ventilation scans, airway appearance at bronchoscopy, and airway pathology were abnormal in the majority of dogs studied. There was a significant relationship between abnormal ventilation scans and abnormal results for PaO2 and end-tidal airflow. Bronchoscopy revealed excessive mucus and inflammation of airway mucosa in all 16 dogs undergoing this procedure. Endoscopically obtained aerobic bacterial cultures grew mixed bacterial flora in only three dogs. Increased numbers of neutrophils in 14 dogs were detected by airway lavage cytology. A large number of eosinophils were seen in airway lavages obtained from two dogs; these two dogs also had evidence for eosinophilic bronchitis on endobronchial biopsy. Oral bronchodilator administration resulted in clinical and expiratory airflow improvements in most dogs, but had no effect on PaO2 or on the radioaerosol-scan abnormalities. The presence of both the physiologic and pathologic airway abnormalities of chronic bronchitis in dogs presented to a veterinary hospital with chronic unexplained cough was confirmed, suggesting that aerobic bacteria do not play an etiologic role in most cases.