Animal Models

There is a need for alternative management strategies in patients whose asthma is inadequately controlled on inhaled corticosteroids. Toward and colleagues examined two models of guinea pig models of airway disease: guinea pigs exposed to LPS or sensitized guinea pigs with atopy exposed to ovalbumen. Sildenafil (Viagra; Pfizer, Morris Plains, NJ) attenuated allergen- and LPS-induced airway hyperresponsiveness and inflammatory cell influx by a mechanism that appeared to be independent of endogenous nitric oxide. The authors call for clinical trials of phosphodiesterase-5 inhibitors in asthma and chronic obstructive pulmonary disease (COPD).

Infection with respiratory syncytial virus (RSV) has been associated with wheezing and childhood asthma, together with increased mucus production. In a murine model of prolonged airway responsiveness induced by RSV in animals that had allergic sensitization with ovalbumin, Hashimoto and colleagues measured the expression of the mucin production genes Muc-5ac and gob-5 by histochemical analysis of lung tissue stained with antimucin antibodies and Western blot analysis to determine the mechanisms by which RSV infection induces airway hyperresponsiveness. Animals infected with RSV only had little expression of the two mucin production genes, whereas animals sensitized with ovalbumin and exposed during 5 days had increased expression, which was enhanced by concomitant RSV infection, but not inoculation with inactivated RSV. IL-10 levels were not associated with mucin production. However, increased lung levels of IL-17 after Day 5 were associated with increased expression of mucin genes in sensitized mice, but not in animals with RSV infection only. The results suggest that RSV infection in the presence of allergic inflammation may worsen airway responsiveness via increased expression of mucus production genes.

Protein tyrosine kinase–signaling cascade plays a pivotal role in activation of inflammatory cells. In a guinea pig model of asthma, Duan and coworkers  studied the effects of a genistein, an inhibitor of protein tyrosine kinase, on airway inflammation. Aerosolized ovalbumin induced acute bronchoconstriction in a dose-dependent manner. Genistein markedly inhibited the bronchoconstriction induced by ovalbumin, but not the bronchoconstriction induced by histamine or methacholine. Genistein also significantly reduced the ovalbumin-induced increases in total cell counts and eosinophils in bronchoalveolar fluid, airway eosinophilia, eosinophil peroxidase activity, and airway hyperactivity. Immunoblot analysis revealed that genistein inhibited the tyrosine phosphorylation induced by epidermal growth factor. The authors conclude that inhibition of the tyrosine kinase–signaling cascade may prove effective in the treatment of asthma.

To determine the role of endogenous histamine in the recruitment of eosinophils and airway hyperresponsiveness, Koarai and coworkers  used knockout mice with disruption of the gene for L-histidine decarboxylase. In wild-type mice sensitized to ovalbumin, inhalation of ovalbumin caused accumulation of eosinophils in the lung, enhanced proliferation of eosinophils in the bone marrow, and increased airway hyperresponsiveness to methacholine. In the knockout mice, airway hyperresponsiveness to methacholine was not altered, but eosinophil proliferation in the bone marrow and eosinophil recruitment to the lung was significantly reduced. Induction of P-selectin in the lung after ovalbumin challenge was also decreased in the knockout mice. The authors conclude that endogenous histamine is involved in the accumulation of eosinophils in the airways after allergic challenge, possibly acting in the bone marrow and producing P-selectin in the airways, and that airway hyperresponsiveness occurs independently of airway eosinophilia.

To examine the proinflammatory and antiinflammatory actions of nitric oxide in bronchial asthma, Jibiki and coworkers studied molecular mechanisms for the activation of activator protein-1 (by nitric oxide) in human bronchial epithelial cells. The reactive nitrogen–generating species, NOR-1, induced the activation of activator protein-1, and this activation was attenuated by a nitric oxide scavenger (carboxyl-PTIO) and by transient transfection of the dominant negative form of apoptosis signal–regulating kinase 1. The reactive nitrogen–generating species, NOR-1, phosphorylated apoptosis signal–regulating kinase 1, c-Jun-NH₂–terminal kinase (JNK), and p38 mitogen–activated protein kinase. In stable endothelial cells of the porcine artery transfected with apoptosis signal–regulating kinase 1, activity of activator protein-1 and phosphorylation of c-Jun-NH₂–terminal kinase and p38 mitogen–activated protein kinase were depressed. The authors conclude that nitric oxide is capable of inducing the activation of activator protein-1 in bronchial epithelial cells and that the cascade of apoptosis signal–regulating kinase 1 and p38 mitogen–activated protein kinase and c-Jun-NH₂–terminal kinase is involved in the activation.

Because allergen-specific immunotherapy is not available for latex allergy, Hardy and coworkers developed a mouse model of allergen to latex glove allergen, Hev b 5. Mice were immunized with the allergen and the response was compared with the response achieved with ovalbumin immunization. Immunization with Hev b 5 or glove extract elicited hallmarks of pulmonary Type 2 (Th2) helper T cell immune responses: increased serum antigen-specific IgE; eosinophilic infiltrates in lungs; increased interleukin-5 in bronchoalveolar fluid; and mucus hypersecretion by epithelial cells in the airways. The responses were comparable to those achieved by ovalbumin. The authors conclude that the mouse model will enable research into the pulmonary inflammation caused by the major latex glove allergen, Hev b 5.

In a mouse model of lung inflammation induced by immunization with ovalbumin, Koo and coworkers investigated the action of compound A, a nonpeptidyl small-molecule antagonist of very late antigen-4. Intratracheal administration of compound A achieved good occupancy of blood cell receptors for about 8 hours. Intranasal administration achieved dose-dependent inhibition of eosinophilia in bronchiolar lavage fluid; intravenous administration of compound A did not have this effect. Specific staining of major basic protein of eosinophils revealed peribronchiolar infiltration of eosinophils; some eosinophils were also positive for nitrotyrosine. The deposition of major basic protein and nitrotyrosine at the base of the perivascular endothelium indicated degranulation of eosinophils. The authors conclude that intranasal administration of compound A, an antagonist of very late antigen-4, decreased eosinophils and their activation products in a model of lung inflammation.

To determine the role of cyclooxygenase-1 and cyclooxygenase-2 in modulating Th2 response in the allergic airway, Carey and coworkers studied ovalabumin-induced airway allergy in mice with genetic deficiency of each enzyme. The airways of mice lacking cyclooxygenase 1 (COX-1^-/-) contained increased numbers of CD4⁺ and CD8⁺ T cells, exaggerated levels of the Th2 cytokines, interleukin-4, -5, and -13, and increased levels of eotaxin and thymus- and activation-regulated chemokine. The COX-1^-/- mice also exhibited greater allergen-induced bronchoconstriction. Compared with wild-type mice, both the COX-1^-/- and COX-2^-/- mice displayed increased levels of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in the lung. The authors conclude that genetic deficiency of cyclooxygenase-1, but not of cyclooxygenase-2, modulates T cell recruitment, secretion of Th2 cytokines, and airway caliber in the allergic airway.

Chiang and coworkers investigated the effect of dendritic cell-based immunotherapy in modulating the immune response of allergic disease in mice. Dendritic cells were first incubated for 48 hours with ovalbumin, ovalbumin plus ribavirin, or ovalbumin plus one of two oligodeoxynucleotides containing an immunostimulatory DNA sequence (ODN 1826 or ODN 1745). The cells were then injected intravenously into four groups of mice. Seven days later, all mice were immunized with intraperitoneal ovalbumin. Ribavirin and ODN 1826 increased the synthesis of interleukin-12 and inhibited the production of interleukin-10. ODN 1826 also enhanced the expression of B7.1, B7.2, and major histocompatibility complex I and II molecules. Dendritic cells modulated by ribavirin and ODN 1826 downregulated Th2 immune response in vivo and alleviated airway inflammation. The authors conclude that dendritic cells modulated with ribavirin or an oligodeoxynucleotide containing an immunostimulatory DNA sequence can decrease airway inflammation.

The macrolide, rapamycin, has immunosuppressive properties and also inhibits smooth muscle proliferation. Fujitani and Trifilieff compared the effects of SAR 943, a rapamycin derivative, and budesonide in a murine model of airway inflammation. In ovalbumin-sensitized mice, allergen challenge induced increases in interleukin-5, interleukin-4, eosinophils, neutrophils, lymphocytes, cellular fibronectin, lung epithelial cell proliferation, mucus hypersecretion, and hyperreactivity to methacholine. All of these variables were inhibited equally by SAR 943 and budesonide when given intranasally 1 hour before and 24 hours after aerosol challenge. In a primary culture of smooth muscle cells from the human airway, SAR 943 caused dose-dependent inhibition of cell proliferation induced by epidermal growth factor, but did not affect basal proliferation. SAR had no effect on a human bronchial epithelial cell line. The authors conclude that a rapamycin derivative, SAR 943, is as effective as budesonide in inhibiting both lung inflammation and remodeling in a murine model of asthma.

To investigate the effects of macrolide antibiotics on mucus hypersecretion, Shimizu and coworkers induced hypertrophy and metaplasia of goblet cells in the nasal epithelium by intranasal instillation of ovalbumin in ovalbumin-sensitized rats and by instillation of lipopolysaccharide. Oral clarithromycin inhibited the mucus production induced by ovalbumin and lipopolysaccharide (ampicillin and josamycin had no effect). Clarithromycin and erythromycin inhibited mucus secretion that occurred spontaneously or in response to tumor necrosis factor- in airway epithelial cells (NCI-H292 cells or human nasal epithelial cells). Expression of MUC5AC messenger RNA was also inhibited. The authors conclude that the macrolide antibiotics, clarithromycin and erythromycin, directly inhibit the secretion of mucus by airway epithelial cells.

In a state of the art review article, Kinnula and Crapo discuss superoxide dismutase in lung disease.

In a pulmonary perspective, Turino and Cantor discuss the role of hyaluronan in respiratory injury and repair.

Citations 1-14 of 14 total displayed.

Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma

Rakesh K. Kumar, Cristan Herbert, Dianne C. Webb, Lily Li, and Paul S. Foster
Am. J. Respir. Crit. Care Med. 170: 1043 -1048. First published online as doi:10.1164/rccm.200405-681OC [Abstract] [Full text]  

Respiratory Syncytial Virus in Allergic Lung Inflammation Increases Muc5ac and Gob-5

Koichi Hashimoto, Barney S. Graham, Samuel B. Ho, Kenneth B. Adler, Robert D. Collins, Sandra J. Olson, Weisong Zhou, Tatsuo Suzutani, Phillip W. Jones, Kasia Goleniewska, Jamye F. O'Neal, and R. Stokes Peebles, Jr.
Am. J. Respir. Crit. Care Med. 170: 306 -312. First published online as doi:10.1164/rccm.200301-030OC [Abstract] [Full text]  

Effect of Phosphodiesterase-5 Inhibitor, Sildenafil (Viagra), in Animal Models of Airways Disease

Toby J. Toward, Nicola Smith, and Kenneth J. Broadley
Am. J. Respir. Crit. Care Med. 169: 227 -234. First published online as doi:10.1164/rccm.200211-1372OC [Abstract] [Full text]  

Ribavirin or CpG DNA Sequence–Modulated Dendritic Cells Decrease the IgE Level and Airway Inflammation

Dian-Jung Chiang, Yi-Ling Ye, Wei-Li Chen, Yueh-Lun Lee, Ni-Yun Hsu, and Bor-Luen Chiang
Am. J. Respir. Crit. Care Med. 168: 575-580. [Abstract] [Full text]  

In Vivo and In Vitro Effects of Macrolide Antibiotics on Mucus Secretion in Airway Epithelial Cells

Takeshi Shimizu, Shino Shimizu, Reiko Hattori, Esteban C. Gabazza, and Yuichi Majima
Am. J. Respir. Crit. Care Med. 168: 581 -587. First published online as doi:10.1164/rccm.200212-1437OC [Abstract] [Full text]  

Superoxide Dismutases in the Lung and Human Lung Diseases

Vuokko L. Kinnula and James D. Crapo
Am. J. Respir. Crit. Care Med. 167: 1600-1619. [Abstract] [Full text]  

Accentuated T Helper Type 2 Airway Response after Allergen Challenge in Cyclooxygenase-1^-/- but Not Cyclooxygenase-2^-/- Mice

Michelle A. Carey, Dori R. Germolec, J. Alyce Bradbury, Rebecca A. Gooch, Michael P. Moorman, Gordon P. Flake, Robert Langenbach, and Darryl C. Zeldin
Am. J. Respir. Crit. Care Med. 167: 1509 -1515. First published online as doi:10.1164/rccm.200211-1383OC [Abstract] [Full text]  

Characterization of a Mouse Model of Allergy to a Major Occupational Latex Glove Allergen Hev b 5

Charles L. Hardy, Linda Kenins, Alexander C. Drew, Jennifer M. Rolland, and Robyn E. O'Hehir
Am. J. Respir. Crit. Care Med. 167: 1393 -1399. First published online as doi:10.1164/rccm.200209-1002OC [Abstract] [Full text]  

A Small Molecule Very Late Antigen–4 Antagonist Can Inhibit Ovalbumin-induced Lung Inflammation

Gloria C. Koo, Kashmira Shah, Gloria J. F. Ding, Jianying Xiao, Richard Wnek, George Doherty, Xin Chun Tong, R. Blake Pepinsky, Ko-Chung Lin, William K. Hagmann, Douglas Kawka, and Irwin I. Singer
Am. J. Respir. Crit. Care Med. 167: 1400 -1409. First published online as doi:10.1164/rccm.200207-696OC [Abstract] [Full text]  

Hyaluronan in Respiratory Injury and Repair

Gerard M. Turino and Jerome O. Cantor
Am. J. Respir. Crit. Care Med. 167: 1169-1175. [Full text]  

Apoptosis Signal-Regulating Kinase 1–Mediated Signaling Pathway Regulates Nitric Oxide–Induced Activator Protein-1 Activation in Human Bronchial Epithelial Cells

Itsuro Jibiki, Shu Hashimoto, Shuichiro Maruoka, Yasuhiro Gon, Atsushi Matsuzawa, Hideki Nishitoh, Hidenori Ichijo, and Takashi Horie
Am. J. Respir. Crit. Care Med. 167: 856-861. [Abstract] [Full text]  

Disruption of L-Histidine Decarboxylase Reduces Airway Eosinophilia but not Hyperresponsiveness

Akira Koarai, Masakazu Ichinose, Satsuki Ishigaki-Suzuki, Shunsuke Yamagata, Hisatoshi Sugiura, Eiko Sakurai, Yoko Makabe-Kobayashi, Atsuo Kuramasu, Takehiko Watanabe, Kunio Shirato, Toshio Hattori, and Hiroshi Ohtsu
Am. J. Respir. Crit. Care Med. 167: 758 -763. First published online as doi:10.1164/rccm.200206-619OC [Abstract] [Full text]  

Antiinflammatory Effects of Genistein, a Tyrosine Kinase Inhibitor, on a Guinea Pig Model of Asthma

Wei Duan, I. Chun Kuo, Sathiyamoorthy Selvarajan, Kaw Yan Chua, Boon Huat Bay, and W. S. Fred Wong
Am. J. Respir. Crit. Care Med. 167: 185 -192. First published online as doi:10.1164/rccm.200205-420OC [Abstract] [Full text]  

In Vivo and In Vitro Effects of SAR 943, a Rapamycin Analogue, on Airway Inflammation and Remodeling

Yasushi Fujitani and Alexandre Trifilieff
Am. J. Respir. Crit. Care Med. 167: 193 -198. First published online as doi:10.1164/rccm.200205-455OC [Abstract] [Full text]