______________________________________________________________________Development of new therapeutics for chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), which pose a huge public health burden 1 , have been hindered by the inability to study organ-level complexities of lung inflammation in vitro. While hospitalization and mortality due to these diseases are often the consequences of exacerbations triggered by pathogens 2, 3 , there is currently no way to study these processes in human lung outside of the clinical setting. Animal models of asthma and COPD exist; however, their clinical relevance is questionable because the anatomy, immune system and inflammatory responses exhibited by animal lungs differ greatly from those in humans [4][5][6] . For example, mucin-producing cells, which are central to the development of asthma, are less frequent in the respiratory tree of mice and rats compared with humans 6 . Neutrophils that increase dramatically in the lungs of patients with COPD and severe asthma 7-9 also comprise only 10-25% of circulating leukocytes in mice, whereas they represent 50-70% in humans 5 . Because many animal models fail to predict drug activities in humans, the pharmaceutical and biotechnology industries strive to reduce or replace animal models for drug testing whenever possible 10 .Airway inflammatory diseases have been modeled in vitro using cultures of primary or immortalized human epithelial cells, sometimes positioned at an air-liquid interface to induce epithelial differentiation 11 or using co-cultures of airway epithelium and tissue-resident immune cells (e.g., macrophages or dendritic cells) 12 . However, lung inflammation is mediated by organ-level responses that involve complex tissuetissue interactions between the lung airway epithelium and underlying microvascular endothelium that modulate immune reactions to respiratory pathogens and allergens [13][14][15] and alter the vascular cell adhesion molecular machinery that recruits circulating immune cells, such as neutrophils. This is important because neutrophil accumulation in the lung is associated with enhanced severity of airflow limitation in COPD patients 7 and it plays a critical role in severe asthma as well 8 . Unfortunately, it is not possible to study complex interactions among airway epithelium, endothelium and circulating neutrophils using existing in vitro lung models because most fail to recapitulate normal functional coupling between the epithelium and endothelium, and none enable analysis of recruitment of circulating immune cells under active fluid flow. This latter point is crucial because neutrophil adhesion to inflamed endothelium involves initial rolling along the luminal surface of endothelium mediated by E-selectin, which is then followed by firm adhesion to and this dynamic shear stress-dependent response cannot be studied in a physiologically relevant way using static cell cultures.Advances in microsystems engineering have recently made it possible to create bio...

Maternal asthma is a risk factor for development of asthma in children, but mechanisms remain unclear. Offspring of asthmatic mother mice (sensitized and repeatedly exposed to OVA Ag) showed airway hyperresponsiveness and allergic pulmonary inflammation after an intentionally suboptimal OVA sensitization and exposure protocol that had little effect on normal offspring. Similar results were obtained when offspring of OVA-allergic mothers were exposed to an unrelated allergen, casein, indicating that the maternal effect is allergen independent and not transferred by OVA-specific Abs. Premating treatment with neutralizing anti-IL-4 Ab or reduction of maternal allergen exposure abrogated the maternal effect, showing a critical mechanistic role for IL-4 and suggesting an additional benefit of allergen avoidance.

Exacerbated inflammation is now recognized as an important component of cystic fibrosis (CF) airway disease. Whether inflammation is part of the basic defect in CF or a response to persistent infection remains controversial. We addressed this question using human fetal tracheal grafts in severe combined immunodeficient mice. This model yields histologically mature, and most importantly, naive CF and non-CF surrogate airways. Significant inflammatory imbalance was found in naive CF airway grafts, including a highly increased intraluminal interleukin 8 content (CF: 10.1 +/- 2.2 ng/ml; non-CF: 1.2 +/- 0.6 ng/ml; P < 0.05) and consistent accumulation of leukocytes in the subepithelial region (P < 0.001). CF airway grafts were not histologically affected until challenged with Pseudomonas aeruginosa, which provoked: (1) early (before 3 h) and massive leukocyte transepithelial migration, (2) intense epithelial exfoliation, and (3) rapid progression of bacteria toward the lamina propria. In non-CF grafts, these three sets of events were not observed before 6 h. Using a model of naive human airways, we thus demonstrate that before any infection, CF airways are in a proinflammatory state. After infection, the basal inflammatory imbalance contributes to exert severe damage to the mucosa, paving the way for bacterial colonization and subsequent steps of CF airway disease.