American Journal of Respiratory Cell and Molecular Biology

Shapiro, Steven D.

doi: 10.1165/rcmb.f277pmid: 14500252

Chow, Chung-Wai; Herrera Abreu, Maria Teresa; Suzuki, Tomoko; Downey, Gregory P.

doi: 10.1165/rcmb.f278pmid: 14500253

Younger, John G.; Shankar-Sinha, Sunita; Mickiewicz, Marc; Brinkman, Adam S.; Valencia, Gabriel A.; Sarma, J. Vidya; Younkin, Ellen M.; Standiford, Theodore J.; Zetoune, Firas S.; Ward, Peter A.

doi: 10.1165/rcmb.2002-0145oc

Erjefält, Jonas S.; Korsgren, Magnus; Malm-Erjefält, Monika; Conroy, Dolores M.; Williams, Timothy J.; Persson, Carl G. A.

doi: 10.1165/rcmb.2003-0015ocpmid: 12663331

Traditionally, traffic and activation of eosinophils in asthmatic airways are thought to take place during the late-phase allergic reaction. The present study tests the hypothesis that when eosinophils are present in the tissue before allergen exposure, as in chronically inflamed asthmatic airways, acute anaphylactic reactions initiate an eosinophil response. Using a guinea-pig allergic model, where eosinophilia is present at baseline conditions, the traffic of resident eosinophils was examined in vivo immediately after allergen challenge. By 2 min after challenge, eosinophils had moved up to apical epithelial positions. Within 10 min, a marked migration of eosinophils into the airway lumen was demonstrated. Along with the allergen-induced egression of eosinophils, acute luminal entry of plasma proteins and eotaxin occurred. Eosinophil egression was effectively inhibited by the antiexudative drug formoterol, whereas the proexudative drug bradykinin could in naive animals evoke a prompt luminal entry of eosinophils. In conclusion, the present study demonstrates that acute allergic reactions initiate a prompt transepithelial migration of resident eosinophils. Our data further suggest that this response in part is initiated by the plasma exudation response, which may alter the transepithelial gradient of eosinophil chemoattractants including eotaxin. We propose that prompt eosinophil response is a significant component of the acute phase of allergic reactions when occurring in airways where these cells are already present in the mucosa.

Pascaud, Marie-Aude; Griscelli, Frank; Raoul, William; Marcos, Elisabeth; Opolon, Paule; Raffestin, Bernadette; Perricaudet, Michael; Adnot, Serge; Eddahibi, Saadia

doi: 10.1165/rcmb.2002-0120ocpmid: 12714372

Nikolaidis, Nikolaos M.; Zimmermann, Nives; King, Nina E.; Mishra, Anil; Pope, Samuel M.; Finkelman, Fred D.; Rothenberg, Marc E.

doi: 10.1165/rcmb.2002-0309ocpmid: 12702542

Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research, underscoring the need for new scientific inquiry. In an effort to provide unbiased insight into the pathogenesis of this disease, we took an empirical approach involving transcript expression profiling of lung tissue from mice with experimental asthma. Employing asthma models induced by different allergens (ovalbumin [OVA] and Aspergillus fumigatus), we found strong induction of trefoil factor-2 (TFF2), a gene involved in epithelial restitution and mucosal secretion in the gastrointestinal tract. Using a combination of pharmacologic delivery and transgenic overexpression, TFF2 was demonstrated to be strongly induced in the lung by interleukin (IL)-4 and IL-13. Notably, TFF2 induction by both OVA and pharmacologic delivery of IL-4 and IL-13 was dependent upon signal transducer and activator of transcription (STAT)6. However, the upregulation of TFF2 by both chronic expression of IL-4 and Aspergillus fumigatus antigen was independent of STAT6. These results establish that TFF2 is an allergen-induced lung gene product differentially regulated by Th2 cytokines and STAT6. Given the important role of trefoil factors in wound healing, epithelial restitution, and maintenance of mucosal integrity in the gastrointestinal tract, these results support a potential role for TFF2, in both the acute and chronic phase of experimental asthma, via separate induction pathways.

Wang, Zhiqian; Lannér, M. Carita; Jin, Najia; Swartz, Darl; Li, Liang; Rhoades, Rodney A.

doi: 10.1165/rcmb.2002-0157ocpmid: 12714374

Rho-kinase was recently found to phosphorylate the myosin-binding subunit (MBS) of myosin phosphatase (MP) and to regulate MP activity. Although myosin light chain (MLC) phosphorylation in pulmonary arterial smooth muscle cells (PASMCs) is thought to be the cellular/molecular basis for hypoxic pulmonary vasoconstriction (HPV), very little is known about the role that Rho-kinase/MP plays in HPV. Rat PASMCs were cultured and made hypoxic (PO 2 = 23 ± 2 mm Hg). Cells exposed to normoxia (PO 2 ∼ 148 mm Hg) served as controls. PASMCs exposed to hypoxia showed a significant increase in MLC and MBS phosphorylation, and a significant decrease in MP activity. Rho-kinase inhibitors (HA1077 or Y-27632) blocked hypoxia-induced MP inactivation and inhibited the hypoxia-induced MLC phosphorylation. Hypoxia was also found to induce stress fiber formation and actin polymerization in cultured PASMCs. In summary, these data show that MP inhibition in PASMCs is linked to activation of Rho-kinase, and that hypoxia inhibits the MP signaling pathway via Rho-kinase.

Floreani, Anthony A.; Wyatt, Todd A.; Stoner, Julie; Sanderson, Sam D.; Thompson, Ethan G.; Allen-Gipson, Diane; Heires, Art J.

doi: 10.1165/rcmb.2002-0143ocpmid: 12714373

The human bronchial epithelial cell is one of the first cell types to be exposed to the irritants and toxins present in inhaled cigarette smoke. The ability of the bronchial epithelium to modulate inflammatory and immune events in response to cigarette smoke is important in the pathogenesis of smoke-induced airway injury. We have shown that cigarette smoke extract and the complement anaphylatoxin C5a both independently induce increased expression of intercellular adhesion molecule (ICAM)-1 on airway epithelial monolayers compared with unstimulated cells in vitro. This enhanced ICAM-1 expression is associated with a greater capacity of the airway epithelial cells to bind mononuclear cells, a process that appears to require the proinflammatory cytokine tumor necrosis factor-α and protein kinase C intracellular signaling. Exposure of epithelial monolayers to the combination of cigarette smoke followed by C5a results in an additive response for ICAM-1 expression and mononuclear cell adhesion compared with smoke or C5a challenge alone. Inhibiting C5a receptor expression can attenuate these responses. These findings suggest that smoke exposure in some way enhances the functional responsiveness of the C5a receptor expressed on these airway epithelial cells for subsequent C5a-mediated increases in ICAM-1 expression and mononuclear cell adhesion. Our results may help explain the initiation and propagation of inflammatory events in vivo induced by chronic airway exposure to cigarette smoke.

Gern, James E.; Brockman-Schneider, Rebecca; Bhattacharya, Saswati; Malter, James S.; Busse, William W.

doi: 10.1165/rcmb.2002-0306ocpmid: 12714378

Viral respiratory infections rapidly increase vascular permeability, which leads to the transudation of serum proteins into airway secretions and tissues. To determine whether this process activates airway epithelial cells, bronchial epithelial cells were incubated with serum, and interleukin (IL)-8 secretion and gene expression were examined. As little as 0.1% serum significantly enhanced IL-8 secretion, and maximal secretion (65 ± 4 ng/ml, 48 h) was observed with 10% serum. Low-density lipoprotein, but not albumin or immunoglobulin G, augmented bronchial epithelial IL-8 secretion, which was partially blocked by a monoclonal antibody specific for the low-density lipoprotein receptor. The IL-8–inducing activity of plasma was also augmented by clotting and platelet activation. Mechanistically, serum activated nuclear factor-κB and increased the stability and steady state levels of IL-8 mRNA. In summary, specific components of serum are potent activators of IL-8 mRNA and secretion, and the increased IL-8 production is likely to be a result of both increased transcription and mRNA stability. This effect may represent an innate mechanism for the recruitment of neutrophils to the airway in response to noxious stimuli, such as viral infections, that increase vascular permeability.

Moodley, Yuben P.; Misso, Neil L. A.; Scaffidi, Amelia K.; Fogel-Petrovic, Mirjana; McAnulty, Robin J.; Laurent, Geoffrey J.; Thompson, Philip J.; Knight, Darryl A.

doi: 10.1165/rcmb.2002-0262ocpmid: 12714376