Epidemiological studies indicate the incidence of asthma is increased in obese and overweight humans. Responses to ozone (O₃), an asthma trigger, are increased in obese ( ob/ob) mice lacking the satiety hormone leptin. The long form of leptin receptor (Ob-R_b) is required for satiety; mice lacking this receptor ( db/db mice) are also substantially obese. Here, wild-type (WT) and db/ db mice were exposed to air or O₃ (2 ppm) for 3 h. Airway responsiveness, measured by the forced oscillation technique, was greater in db/db than WT mice after air exposure. O₃-induced increases in pulmonary resistance and airway responsiveness were also greater in db/ db mice. BALF eotaxin, IL-6, KC, and MIP-2 increased 4 h after O₃ exposure and subsided by 24 h, whereas protein and neutrophils continued to increase through 24 h. For each outcome, the effect of O₃ was significantly greater in db/ db than WT mice. Previously published results obtained in ob/ob mice were similar except for O₃-induced neutrophils and MIP-2, which were not different from WT mice. O₃ also induced pulmonary IL-1β and TNF-α mRNA expression in db/db but not ob/ob mice. Leptin was increased in serum of db/db mice, and pulmonary mRNA expression of short form of leptin receptor (Ob-R_a) was similar in db/db and WT mice. These data confirm obese mice have innate airway hyperresponsiveness and increased pulmonary responses to O₃. Differences between ob/ob mice, which lack leptin, and db/db mice, which lack Ob-R_b but not Ob-R_a, suggest leptin, acting through Ob-R_a, can modify some pulmonary responses to O₃.

Rationale: Epidemiologic data indicate an increased incidence of asthma in the obese. Objectives: To determine whether obese mice exhibit augmented pulmonary responses after allergen sensitization and challenge. Methods: Lean, wild-type (C57BL/6), obese ob/ob, and obese db/db mice were sensitized to ovalbumin (OVA), and then challenged with aerosolized OVA or phosphate-buffered saline (PBS). Changes in total pulmonary resistance (Rl) induced by intravenous methacholine were measured by forced oscillation. Blood was collected, bronchoalveolar lavage (BAL) was performed, and lungs were harvested for measurement of cytokine expression by real-time reverse transcription–polymerase chain reaction. Measurements and Main Results: OVA challenge increased baseline Rl in ob/ob, but not wild-type, mice, and airway responsiveness was greater in ob/ob than wild-type mice, regardless of the challenge. Compared with PBS, OVA challenge caused an increase in the number of BAL fluid (BALF) cells, an increase in lung Th2 cytokine expression, and an increase in serum IgE. Significantly fewer BALF cells were recovered from OVA-challenged ob/ob versus wild-type mice, whereas serum IgE levels were elevated significantly more in ob/ob versus wild-type mice. BALF and lung Th2 cytokine expression was not different in ob/ob versus wild-type mice. Airway responsiveness was greater in db/db versus wild-type mice, regardless of the challenge, and OVA caused airway hyperresponsiveness in db/db but not wild-type mice, despite reduced BALF cells in OVA-challenged db/db versus wild-type mice. Conclusions: These results demonstrate that obesity enhances OVA-induced changes in pulmonary resistance and serum IgE and that these changes are not the result of increased Th2 type airway inflammation.

We previously reported that genetically obese mice exhibit innate airway hyperresponsiveness (AHR) and enhanced ozone (O₃)-induced pulmonary inflammation. Such genetic deficiencies in mice are rare in humans, and they may not be representative of human obesity. Thus the purpose of this study was to determine the pulmonary phenotype of mice with diet-induced obesity (DIO), which more closely mimics the cause of human obesity. Therefore, wild-type C57BL/6 mice were reared from the time of weaning until at least 30 wk of age on diets in which either 10 or 60% of the calories are derived from fat in the form of lard. Body mass was ∼40% greater in mice fed 60 vs. 10% fat diets. Baseline airway responsiveness to intravenous methacholine, measured by forced oscillation, was greater in mice fed 60 vs. 10% fat diets. We also examined lung permeability and inflammation after exposure to room air or O₃ (2 parts/million for 3 h), an asthma trigger. Four hours after the exposure ended, O₃-induced increases in bronchoalveolar lavage fluid protein, interleukin-6, KC, macrophage inflammatory protein-2, interferon-γ-inducible protein-10, and eotaxin were greater in mice fed 60 vs. 10% fat diets. Innate AHR and augmented responses to O₃ were not observed in mice raised from weaning until 20–22 wk of age on a 60% fat diet. These results indicate that mice with DIO exhibit innate AHR and enhanced O₃-induced pulmonary inflammation, similar to genetically obese mice. However, mice with DIO must remain obese for an extended period of time before this pulmonary phenotype is observed.

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.

A 15-month-old boy presenting with hand, foot and mouth disease died of myocarditis and intractable shock caused by coxsackievirus A16 infection. It is apparent that coxsackievirus A16 infection is not always a benign infection.