The Role of Extreme Weather and Climate-Related Events on Asthma Outcomes.

Extreme weather and climate events are likely to increase in frequency and severity as a consequence of global climate change. These are events that can include flooding rains, prolonged heat waves, drought, wildfires, hurricanes, severe thunderstorms, tornadoes, storm surge, and coastal flooding. It is important to consider these events as they are not merely meteorologic occurrences but are linked to our health. We aim to address how these events are interconnected with asthma outcomes associated with thunderstorm asthma, pollen production, mold infestation from flooding events, and poor air quality during wildfires.

Combined Collagen-Induced Arthritis and Organic Dust-Induced Airway Inflammation to Model Inflammatory Lung Disease in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is characterized by extra-articular involvement including lung disease, yet the mechanisms linking the two conditions are poorly understood. The collagen-induced arthritis (CIA) model was combined with the organic dust extract (ODE) airway inflammatory model to assess bone/joint-lung inflammatory outcomes. DBA/1J mice were intranasally treated with saline or ODE daily for 5 weeks. CIA was induced on days 1 and 21. Treatment groups included sham (saline injection/saline inhalation), CIA (CIA/saline), ODE (saline/ODE), and CIA + ODE (CIA/ODE). Arthritis inflammatory scores, bones, bronchoalveolar lavage fluid, lung tissues, and serum were assessed. In DBA/1J male mice, arthritis was increased in CIA + ODE > CIA > ODE versus sham. Micro-computed tomography (µCT) demonstrated that loss of BMD and volume and deterioration of bone microarchitecture was greatest in CIA + ODE. However, ODE-induced airway neutrophil influx and inflammatory cytokine/chemokine levels in lavage fluids were increased in ODE > CIA + ODE versus sham. Activated lung CD11c+ CD11b+ macrophages were increased in ODE > CIA + ODE > CIA pattern, whereas lung hyaluronan, fibronectin, and amphiregulin levels were greatest in CIA + ODE. Serum autoantibody and inflammatory marker concentrations varied among experimental groups. Compared with male mice, female mice showed less articular and pulmonary disease. The interaction of inhalation-induced airway inflammation and arthritis induction resulted in compartmentalized responses with the greatest degree of arthritis and bone loss in male mice with combined exposures. Data also support suppression of the lung inflammatory response, but increases in extracellular matrix protein deposition/interstitial disease in the setting of arthritis. This coexposure model could be exploited to better understand and treat RA-lung disease. © 2019 American Society for Bone and Mineral Research.

Sex differences impact the lung-bone inflammatory response to repetitive inhalant lipopolysaccharide exposures in mice.

Skeletal health consequences associated with inflammatory diseases of the airways significantly contribute to morbidity. Sex differences have been described independently for lung and bone diseases. Repetitive inhalant exposure to lipopolysaccharide (LPS) induces bone loss and deterioration in male mice, but comparison effects in females are unknown. Using an intranasal inhalation exposure model, 8-week-old C57BL/6 male and female mice were treated daily with LPS (100 ng) or saline for 3 weeks. Bronchoalveolar lavage fluids, lung tissues, tibias, bone marrow cells, and blood were collected. LPS-induced airway neutrophil influx, interleukin (IL)-6 and neutrophil chemoattractant levels, and bronchiolar inflammation were exaggerated in male animals as compared to female mice. Trabecular bone micro-CT imaging and analysis of the proximal tibia were conducted. Inhalant LPS exposures lead to deterioration of bone quality only in male mice (not females) marked by decreased bone mineral density, bone volume/tissue volume ratio, trabecular thickness and number, and increased bone surface-to-bone volume ratio. Serum pentraxin-2 levels were modulated by sex differences and LPS exposure. In proof-of-concept studies, ovarectomized female mice demonstrated LPS-induced bone deterioration, and estradiol supplementation of ovarectomized female mice and control male mice protected against LPS-induced bone deterioration findings. Collectively, sex-specific differences exist in LPS-induced airway inflammatory consequences with significant differences found in bone quantity and quality parameters. Male mice demonstrated susceptibility to bone loss and female animals were protected, which was modulated by estrogen. Therefore, sex differences influence the biologic response in the lung-bone inflammatory axis in response to inhalant LPS exposures.

The Effect of Inhalant Organic Dust on Bone Health.

PURPOSE OF REVIEW: Agriculture remains a major economic sector globally, and workers experience high rates of chronic inflammatory lung and musculoskeletal diseases. Whereas obstructive pulmonary diseases are known risk factors for bone loss, the underlying relationship between lung inflammation and bone health is not well known. RECENT FINDINGS: An agriculture organic dust extract inhalation animal model has recently linked lung injury-induced inflammation to systemic bone loss. This process is dependent upon lipopolysaccharide and the toll-like receptor 4 (TLR4) signaling pathway. Downstream systemic interleukin-6 is a key mediator that subsequently activates osteoclastogenesis. Age is a host factor that impacted bone disease with younger mice demonstrating increased susceptibility to bone loss following inhalant exposures as compared to older mice. Supplemental dietary vitamin D was shown to prevent organic dust-induced bone loss, but not lung disease, in animals. Recent animal studies provide new mechanistic insight into the lung-bone inflammatory axis. Host factors, diet, and lipopolysaccharide/TLR4 signaling pathways play a significant role in explaining how inhalant organic dust exposures impact bone health. These investigations might lead to specific targeted therapeutic approaches.

ß2-Adrenergic agonists attenuate organic dust-induced lung inflammation.

Agricultural dust exposure results in significant lung inflammation, and individuals working in concentrated animal feeding operations (CAFOs) are at risk for chronic airway inflammatory diseases. Exposure of bronchial epithelial cells to aqueous extracts of hog CAFO dusts (HDE) leads to inflammatory cytokine production that is driven by protein kinase C (PKC) activation. cAMP-dependent protein kinase (PKA)-activating agents can inhibit PKC activation in epithelial cells, leading to reduced inflammatory cytokine production following HDE exposure. ß2-Adrenergic receptor agonists (ß2-agonists) activate PKA, and we hypothesized that ß2-agonists would beneficially impact HDE-induced adverse airway inflammatory consequences. Bronchial epithelial cells were cultured with the short-acting ß2-agonist salbutamol or the long-acting ß2-agonist salmeterol prior to stimulation with HDE. ß2-Agonist treatment significantly increased PKA activation and significantly decreased HDE-stimulated IL-6 and IL-8 production in a concentration- and time-dependent manner. Salbutamol treatment significantly reduced HDE-induced intracellular adhesion molecule-1 expression and neutrophil adhesion to epithelial cells. Using an established intranasal inhalation exposure model, we found that salbutamol pretreatment reduced airway neutrophil influx and IL-6, TNF-α, CXCL1, and CXCL2 release in bronchoalveolar lavage fluid following a one-time exposure to HDE. Likewise, when mice were pretreated daily with salbutamol prior to HDE exposure for 3 wk, HDE-induced neutrophil influx and inflammatory mediator production were also reduced. The severity of HDE-induced lung pathology in mice repetitively exposed to HDE for 3 wk was also decreased with daily salbutamol pretreatment. Together, these results support the need for future clinical investigations to evaluate the utility of ß2-agonist therapies in the treatment of airway inflammation associated with CAFO dust exposure.

Vitamin D supplementation protects against bone loss following inhalant organic dust and lipopolysaccharide exposures in mice.

Systemic bone loss is associated with airway inflammatory diseases; yet, strategies to halt disease progression from inhalant exposures are not clear. Vitamin D might be a potentially protective approach against noxious respirable environmental exposures. We sought to determine whether vitamin D supplementation represents a viable lung- and bone-protective strategy following repetitive inhalant treatments with organic dust extract (ODE) or lipopolysaccharide (LPS) in mice. C57BL/5 mice were maintained on diets with low (1 IU/D/g) or high (10 IU/D/g) vitamin D for 5 weeks and treated with ODE from swine confinement facilities, LPS, or saline daily for 3 weeks per established intranasal inhalation protocol. Lungs, hind limbs, and sera were harvested for experimental outcomes. Serum 25-hydroxyvitamin D levels were tenfold different between low and high vitamin D treatment groups with no differences between inhalant agents and saline treatments. Serum calcium levels were not affected. There was no difference in the magnitude of ODE- or LPS-induced inflammatory cell influx or lung histopathology between high and low vitamin D treatment groups. However, high vitamin D treatment reversed the loss of bone mineral density, bone volume, and bone micro-architecture deterioration induced by ODE or LPS as determined by micro-CT analysis. Bone-resorbing osteoclasts were also reduced by high vitamin D treatment. In the low vitamin D treatment groups, ODE induced the greatest degree of airway inflammatory consequences, and LPS induced the greatest degree of bone loss. Collectively, high-concentration vitamin D was protective against systemic bone loss, but not airway inflammation, resulting from ODE- or LPS-induced airway injury.

The omega-3 fatty acid docosahexaenoic acid attenuates organic dust-induced airway inflammation.

Workers exposed to organic dusts from concentrated animal feeding operations (CAFOs) are at risk for developing airway inflammatory diseases. Available preventative and therapeutic measures for alleviating dust-induced lung disease are inadequate. Because omega-3 fatty acids can mitigate inflammatory processes, we aimed to determine whether nutritional supplementation with the omega-3 fatty acid docosahexaenoic acid (DHA) could reduce the airway inflammatory consequences of exposures to organic dust. Aqueous extracts of organic dusts from swine CAFOs (ODE) were utilized. In DHA-pretreated human bronchial epithelial cells, lung fibroblasts, monocyte cell cultures, and precision-cut murine lung slices, we found that DHA pretreatment dose-dependently decreased ODE-induced inflammatory cytokine production. To determine the in vivo significance of DHA, C57BL/6 mice were orally administered DHA for seven days prior to treatment with intranasal ODE or saline inhalations. Animals treated with 2 mg DHA demonstrated significant reductions in ODE-induced bronchial alveolar lavage neutrophil influx and pro-inflammatory cytokine/chemokine production compared to mice exposed to ODE alone. Collectively, these data demonstrate that DHA affects several lung cells to reduce the airway inflammatory response to organic dust exposures. Dietary supplementation with DHA may be an effective therapeutic strategy to reduce the airway inflammatory consequences in individuals exposed to agriculture dust environments.

Vitamin D supplementation: a potential booster for urticaria therapy.

Chronic urticaria is a common skin condition whereby the etiology remains largely idiopathic and the mainstay therapy is symptomatic control with antihistamines. There have been a limited number of small studies suggesting a potential role for vitamin D in chronic urticaria, and this this editorial review will discuss the current supporting evidence. Associations for decreased serum vitamin 25 hydroxyvitamin D levels in subjects with chronic urticaria have been reported. In addition to observational reports, there has been a randomized, prospective, blinded trial demonstrating symptom improvement when high vitamin D3 supplementation was utilized as an add-on therapy for urticarial management. More research is needed to address mechanisms of action and to investigate vitamin D supplementation in larger and longer duration human trials.

Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study.

BACKGROUND: Observational reports have linked vitamin D with chronic urticaria, yet no randomized controlled trial has been conducted. OBJECTIVE: To determine whether high-dose vitamin D supplementation would decrease Urticaria Symptom Severity (USS) scores and medication burden in patients with chronic urticaria. METHODS: In a prospective, double-blinded, single-center study, 42 subjects with chronic urticaria were randomized to high (4,000 IU/d) or low (600 IU/d) vitamin D3 supplementation for 12 weeks. All subjects were provided with a standardized triple-drug therapy (cetirizine, ranitidine, and montelukast) and a written action plan. Data on USS scores, medication use, blood for 25-hydroxyvitamin D, and safety measurements were collected. RESULTS: Triple-drug therapy decreased total USS scores by 33% in the first week. There was a further significant decrease (40%) in total USS scores in the high, but not low, vitamin D3 treatment group by week 12. Compared with low treatment, the high treatment group demonstrated a trend (P = .052) toward lower total USS scores at week 12, which was driven by significant decreases in body distribution and number of days with hives. Beneficial trends for sleep quality and pruritus scores were observed with high vitamin D3. Serum 25-hydroxyvitamin D levels increased with high vitamin D3 supplementation, but there was no correlation between 25-hydroxyvitamin D levels and USS scores. There was no difference in allergy medication use between groups. No adverse events occurred. CONCLUSION: Add-on therapy with high-dose vitamin D3 (4,000 IU/d) could be considered a safe and potentially beneficial immunomodulator in patients with chronic urticaria. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01371877.

Rhinitis associated with pesticide use among private pesticide applicators in the agricultural health study.

Farmers commonly experience rhinitis but the risk factors are not well characterized. The aim of this study was to analyze cross-sectional data on rhinitis in the past year and pesticide use from 21,958 Iowa and North Carolina farmers in the Agricultural Health Study, enrolled 1993-1997, to evaluate pesticide predictors of rhinitis. Polytomous and logistic regression models were used to assess association between pesticide use and rhinitis while controlling for demographics and farm-related exposures. Sixty-seven percent of farmers reported current rhinitis and 39% reported 3 or more rhinitis episodes. The herbicides glyphosate [odds ratio (OR) = 1.09, 95% confidence interval (95% CI) = 1.05-1.13] and petroleum oil (OR = 1.12, 95% CI = 1.05-1.19) were associated with current rhinitis and increased rhinitis episodes. Of the insecticides, four organophosphates (chlorpyrifos, diazinon, dichlorvos, and malathion), carbaryl, and use of permethrin on animals were predictors of current rhinitis. Diazinon was significant in the overall polytomous model and was associated with an elevated OR of 13+ rhinitis episodes (13+ episodes OR = 1.23, 95% CI = 1.09-1.38). The fungicide captan was also a significant predictor of rhinitis. Use of petroleum oil, use of malathion, use of permethrin, and use of the herbicide metolachlor were significant in exposure-response polytomous models. Specific pesticides may contribute to rhinitis in farmers; agricultural activities did not explain these findings.

Inlet patch of gastric mucosa in upper esophagus causing chronic cough and vocal cord dysfunction.

BACKGROUND: An inlet patch of gastric mucosa in the upper esophagus is usually an incidental, congenital finding found during upper gastrointestinal tract endoscopy. Although it has been reported to cause dysphagia, strictures, adenocarcinoma, and webs, it has never been associated with cough and vocal cord dysfunction. OBJECTIVE: To report the first case of a patient with an inlet patch of gastric mucosa in the upper esophagus as the cause of a particularly troublesome, chronic cough that was initially missed on 2 upper endoscopies. METHODS: The patient is a 50-year-old man with a 7-year history of chronic cough associated with hoarseness, shortness of breath, and globus sensation. For diagnostic evaluation, pulmonary function tests, chest computed tomography, rhinolaryngoscopy, upper gastrointestinal tract endoscopy, and histologic examinations were performed. RESULTS: A multidisciplinary approach revealed several possible causes for the chronic cough, including vocal cord dysfunction, postnasal drip syndrome, allergic rhinitis, and mild gastroesophageal reflux disease that was only partially responsive to therapy. The results of 2 initial upper gastrointestinal tract endoscopies were interpreted as normal. A third endoscopy detected an inlet patch of gastric mucosa in the upper esophagus. Treatment with a high-dose histamine type 2 receptor antagonist and a proton pump inhibitor alleviated the patient's symptoms. CONCLUSIONS: An inlet patch of gastric mucosa in the upper esophagus is not uncommon, but it is often overlooked or believed to be an incidental, congenital finding. This is the first report, to our knowledge, of an inlet patch resulting in a troublesome, chronic cough.