Inhaled Wood Smoke Research Articles

Intraperitoneal oxygen microbubble therapy: A novel approach to enhance systemic oxygenation in a smoke inhalation model of acute hypoxic respiratory failure

BackgroundPatients suffering from severe acute respiratory distress syndrome (ARDS) face limited therapeutic options and alarmingly high mortality rates. Refractory hypoxemia, a hallmark of ARDS, often necessitates invasive and high-risk treatments. Oxygen microbubbles (OMB) present a promising approach for extrapulmonary oxygenation, potentially augmenting systemic oxygen levels without exposing patients to significant risks. MethodsRats with severe, acute hypoxemia secondary to wood smoke inhalation (SI) received intraperitoneal (IP) bolus injections of escalating weight-by-volume (BW/V) OMB doses or normal saline to determine optimal dosage and treatment efficacy. Subsequently, a 10 % BW/V OMB bolus or saline was administered to a group of SI rats and a control group of healthy rats (SHAM). Imaging, vital signs, and laboratory studies were compared at baseline, post-smoke inhalation, and post-treatment. Histological examination and lung tissue wet/dry weight ratios were assessed at study conclusion. ResultsTreatment with various OMB doses in SI-induced acute hypoxemia revealed that a 10 % BW/V OMB dose significantly augmented systemic oxygen levels while minimizing dose volume. The second set of studies demonstrated a significant increase in partial pressure of arterial oxygen (PaO2) and normalization of heart rate with OMB treatment in the SI group compared to saline treatment or control group treatment. ConclusionsThis study highlights the successful augmentation of systemic oxygenation following OMB treatment in a small animal model of severe hypoxemia. OMB therapy emerges as a novel and promising treatment modality with immense translational potential for oxygenation support in acute care settings.

Biomass smoke inhalation promotes neuroinflammatory and metabolomic temporal changes in the hippocampus of female mice

Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m3. Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31Hi and CD31Med expressors, with wood smoke inhalation causing an increased proportion of CD31Hi. These populations of CD31Hi and CD31Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b+/CD45low) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD+ metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD+ abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure.

46 Bardoxolone-methyl Microparticles Ameliorate Immune Dysfunction Following Burn and Inhalation Injury Through the NRF2/KEAP1 Axis

IntroductionSevere burn injury leads to many systemic stresses that can seriously impact multiple systems throughout the body. These stresses are further exacerbated if there is a combined burn and inhalation injury, which leads to increased morbidity and mortality for many patients. Combined burn and inhalation injury causes an intense systemic inflammatory response and activation of the innate immune system which can lead to inflammatory complications, such as systemic inflammatory response syndrome and multiple organ failure. Nuclear Factor-Erythroid-2-Related Factor (NRF2) is a transcription factor that acts to downregulate overt damaging pro-inflammatory and oxidative responses and maintain immune homeostasis. This transcription factor remains bound to Kelch-like ECH-associated protein 1 (KEAP1) in the cytoplasm. Under oxidative stress, NRF2 dissociates from KEAP1 and translocates to the nucleus where it facilitates the transcription of anti-inflammatory and antioxidant genes. We hypothesized that NRF2 is a key regulator after burn and inhalation injury, and activation of NRF2 can limit the severity of burn and inhalation injury.MethodsTo test this, we have developed a mouse model of combined cutaneous burn and woodsmoke inhalation injury. After burn and inhalation injury, we found that NRF2-/- knockout mice have higher mortality compared to wild-type (WT) mice and suffer from increased vascular permeability and lung edema, suggesting that this transcription factor is important for controlling morbidity and mortality. In WT mice, NRF2 is activated following burn and inhalation injury, however, based on immunohistochemical staining, it is not sufficiently induced following this insult since it remains in the cytoplasm and is unable to transcribe anti-inflammatory genes. Therefore, we treated WT mice with an intraperitoneal injection of bardoxolone-methyl microparticles, a NRF2 activator that separates KEAP1 from NRF2 in the cytoplasm, immediately after burn and inhalation injury in WT miceResultsWe observed significant decreases in mortality as well as reduced concentrations of certain pro-inflammatory cytokines in the blood and bronchoalveolar-lavage fluid of these mice. In the lungs of these mice, there was an upregulation in numerous pathways involved in the management of inflammation and immune response compared to mice that did not receive bardoxolone-methyl microparticles.ConclusionsIn conclusion, treatment with bardoxolone-methyl microparticles immediately after burn and inhalation injury might be effective for reducing the severity of the inflammatory response and limiting inflammatory complications.

Impact of GSTM1 Genotype on Airway Response to Inhaled Wood Smoke Particles

Impact of GSTM1 Genotype on Airway Response to Inhaled Wood Smoke Particles

Lung function measures following simulated wildland firefighter exposures

ABSTRACTAcross the world, biomass smoke is a major source of air pollution and is linked with a variety of adverse health effects. This is particularly true in the western U.S. where wood smoke from wildland forest fires are a significant source of PM2.5. Wildland firefighters are impacted as they experience elevated PM2.5 concentrations over extended periods of time, often occurring during physical exertion. Various epidemiological studies have investigated wood smoke impacts on human health, including occupational field exposures experienced by wildland firefighters. As there are numerous challenges in carrying out these field studies, having the ability to research the potential health impacts to this occupational cohort in a controlled setting would provide important information that could be translated to the field setting.To this end, we have carried out a simulated wildland firefighter exposure study in a wood smoke inhalation facility. Utilizing a randomized crossover trial design, we exposed 10 participants once to clean filtered-air, 250 µg/m3, and 500 µg/m3 wood stove-generated wood smoke PM2.5. Participants exercised on a treadmill at an absolute intensity designed to simulate wildland firefighting for 1.5 hr. In addition to measured PM2.5 smoke concentrations, mean levels of CO2, CO, and % relative humidity were continuously monitored and recorded and were representative of occupational “real-world” exposures. Pulmonary function was measured at three time points: before, immediately after, and 1-hr post-exposure. Although there were some reductions in FVC, FEV1, and FVC:FEV1 measures, results of the spirometry testing did not show significant changes in lung function. The development of this wood smoke inhalational facility provides a platform to further address unique research questions related to wood smoke exposures and associated adverse health effects.

Measured Pulmonary and Systemic Markers of Inflammation and Oxidative Stress Following Wildland Firefighter Simulations.

A controlled human exposure study was conducted to investigate the impact of inhalational exposures to wood smoke PM2.5 on measured concentrations of airway and systemic inflammatory biomarkers. Mimicking wildland firefighter activities, 10 participants were exposed to three doses of wood smoke PM2.5 (filtered-air, 250 μg/m, and 500 μg/m) while exercising on a treadmill. Exhaled breath condensate (EBC) and blood plasma samples were obtained pre-, immediately post-, and 1-hour postexposure. 8-isoprostane, pH, and myeloperoxidase were measured in EBC, while H2O2, surfactant protein D, and pentraxin-3 (PTX3) were measured in both EBC and plasma. Only pH, 8-isoprostane, and PTX3 displayed significant changes when comparing pre- and postexposures. Markers of inflammation and oxidative stress, including PTX3, pH, and 8-isoprostane in EBC and/or plasma, are sensitive to wood smoke inhalation, with further investigations warranted.

Household air pollution causes dose-dependent inflammation and altered phagocytosis in human macrophages.

Three billion people are exposed to household air pollution from biomass fuel use. Exposure is associated with higher incidence of pneumonia, and possibly tuberculosis. Understanding mechanisms underlying these defects would improve preventive strategies. We used human alveolar macrophages obtained from healthy Malawian adults exposed naturally to household air pollution and compared them with human monocyte-derived macrophages exposed in vitro to respirable-sized particulates. Cellular inflammatory response was assessed by IL-6 and IL-8 production in response to particulate challenge; phagosomal function was tested by uptake and oxidation of fluorescence-labeled beads; ingestion and killing of Streptococcus pneumoniae and Mycobacterium tuberculosis were measured by microscopy and quantitative culture. Particulate ingestion was quantified by digital image analysis. We were able to reproduce the carbon loading of naturally exposed alveolar macrophages by in vitro exposure of monocyte-derived macrophages. Fine carbon black induced IL-8 release from monocyte-derived and alveolar macrophages (P < 0.05) with similar magnitude responses (log10 increases of 0.93 [SEM = 0.2] versus 0.74 [SEM = 0.19], respectively). Phagocytosis of pneumococci and mycobacteria was impaired with higher particulate loading. High particulate loading corresponded with a lower oxidative burst capacity (P = 0.0015). There was no overall effect on killing of M. tuberculosis. Alveolar macrophage function is altered by particulate loading. Our macrophage model is comparable morphologically to the in vivo uptake of particulates. Wood smoke-exposed cells demonstrate reduced phagocytosis, but unaffected mycobacterial killing, suggesting defects related to chronic wood smoke inhalation limited to specific innate immune functions.

Respiratory Tract Deposition of Inhaled Wood Smoke Particles in Healthy Volunteers.

Respiratory tract deposition of air pollution particles is a key to their adverse health effects. This study was aimed to determine the size-resolved deposition fraction (DF) of sooty wood smoke particles in the lungs of healthy subjects. The type of wood smoke investigated is typical for household air pollution from solid fuels, which is among the largest environmental health problems globally. Twelve healthy volunteers inhaled diluted wood smoke from incomplete soot-rich combustion in a common wood stove. The DF of smoke particles (10-500 nm) was measured during three 15-min exposures in each subject during spontaneous breathing. Lung function was measured using standard spirometry. The total DFs by particle number concentration were 0.34±0.08. This can be compared with DFs of 0.21-0.23 in healthy subjects during previous experiments with wood pellet combustion. For particle mass, the total DFs found in this study were 0.22±0.06. DF and breathing frequency were negatively correlated as expected from model calculations (p<0.01). The DF of the investigated sooty wood smoke particles was higher than for previously investigated particles generated during more efficient combustion of biomass. Together with toxicological studies, which have indicated that incomplete biomass combustion particles rich in soot and polycyclic aromatic hydrocarbons (PAHs) are especially harmful, these data highlight the health risks of inadequate wood combustion.

Comparison of airway pressure release ventilation to conventional mechanical ventilation in the early management of smoke inhalation injury in swine*

The role of airway pressure release ventilation in the management of early smoke inhalation injury has not been studied. We compared the effects of airway pressure release ventilation and conventional mechanical ventilation on oxygenation in a porcine model of acute respiratory distress syndrome induced by wood smoke inhalation. Prospective animal study. Government laboratory animal intensive care unit. Thirty-three Yorkshire pigs. Smoke inhalation injury. Anesthetized female Yorkshire pigs (n = 33) inhaled room-temperature pine-bark smoke. Before injury, the pigs were randomized to receive conventional mechanical ventilation (n = 15) or airway pressure release ventilation (n = 12) for 48 hrs after smoke inhalation. As acute respiratory distress syndrome developed (PaO2/Fio2 ratio <200), plateau pressures were limited to <35 cm H2O. Six uninjured pigs received conventional mechanical ventilation for 48 hrs and served as time controls. Changes in PaO2/Fio2 ratio, tidal volume, respiratory rate, mean airway pressure, plateau pressure, and hemodynamic variables were recorded. Survival was assessed using Kaplan-Meier analysis. PaO2/Fio2 ratio was lower in airway pressure release ventilation vs. conventional mechanical ventilation pigs at 12, 18, and 24 hrs (p < .05) but not at 48 hrs. Tidal volumes were lower in conventional mechanical ventilation animals between 30 and 48 hrs post injury (p < .05). Respiratory rates were lower in airway pressure release ventilation at 24, 42, and 48 hrs (p < .05). Mean airway pressures were higher in airway pressure release ventilation animals between 6 and 48 hrs (p < .05). There was no difference in plateau pressures, hemodynamic variables, or survival between conventional mechanical ventilation and airway pressure release ventilation pigs. In this model of acute respiratory distress syndrome caused by severe smoke inhalation in swine, airway pressure release ventilation-treated animals developed acute respiratory distress syndrome faster than conventional mechanical ventilation-treated animals, showing a lower PaO2/Fio2 ratio at 12, 18, and 24 hrs after injury. At other time points, PaO2/Fio2 ratio was not different between conventional mechanical ventilation and airway pressure release ventilation.

Exacerbation of wood smoke-induced acute lung injury by mechanical ventilation using moderately high tidal volume in mice

We investigated the effects of mechanical ventilation with a moderately high tidal volume (VT) on acute lung injury (ALI) induced by wood smoke inhalation in anesthetized mice. Animals received challenges of air, 30 breaths of smoke (30SM) or 60 breaths of smoke (60SM) and were then ventilated with a VT of 10 ml/kg (10VT) or 16 ml/kg (16VT). After 4-h mechanical ventilation, the bronchoalveolar-capillary permeability, pulmonary infiltration of inflammatory cells, total lung injury score and pulmonary expressions of interleukin-1beta and macrophage inflammatory protein-2 mRNA and proteins in the 30SM+16VT and 60SM+16VT groups were greater than those in the 30SM+10VT and 60SM+10VT groups, respectively. Additionally, the wet/dry weight ratio of lung tissues and lung epithelial cell apoptosis in the 60SM+16VT group were greater than those in the 60SM+10VT group. These differences between the 16VT and 10VT groups were not seen in animals with air challenge. Thus, mechanical ventilation with a moderately high VT in mice exacerbates ALI induced by wood smoke inhalation.

Função respiratória em bombeiros portugueses

Introduction: Portugal has had a high rate of forest fires in recent years. Inhaled wood smoke can have short- and long-term effects on the lung function of people exposed to it.Study objectives: To assess the lung function of active wildland (forest) firefighters.Methods: Cross-sectional study. A self-questionnaire on personal and work habits was used and spirometry values were obtained using Piko-6® for a 209 people sample.Results: We found a high rate of smoking (42.9%) and an 11.8% prevalence of obstruction. 41.7% of the obstructed individuals were non-smokers, did not state a knowledge of any respiratory disease, engaged in no other activity that could be related to lung function decrease and did not wear airway protection apparatus. 85.7% did not use any airway protection apparatus when firefighting due to lack of such equipment in their brigades.Conclusions: Data showed that there is a high prevalence of smoking habits in this sample of Portuguese firefighters; there is an unsatisfactory usage of airway protection apparatus and the prevalence of airway obstruction is higher than the COPD prevalence in the Portuguese population. We recommend stopping smoking and use of equipment for respiratory protection.Rev Port Pneumol 2007; XIII (3): 349-364

Pulmonary function in portuguese firefighters

IntroductionPortugal has had a high rate of forest fires in recent years. Inhaled wood smoke can have short- and long-term effects on the lung function of people exposed to it. Study objectivesTo assess the lung function of active wildland (forest) firefighters. MethodsCross-sectional study. A self-questionnaire on personal and work habits was used and spirometry values were obtained using Piko-6® for a 209 people sample. ResultsWe found a high rate of smoking (42.9%) and an 11.8% prevalence of obstruction. 41.7% of the obstructed individuals were non-smokers, did not state a knowledge of any respiratory disease, engaged in no other activity that could be related to lung function decrease and did not wear airway protection apparatus. 85.7% did not use any airway protection apparatus when firefighting due to lack of such equipment in their brigades. ConclusionsData showed that there is a high prevalence of smoking habits in this sample of Portuguese firefighters; there is an unsatisfactory usage of airway protection apparatus and the prevalence of airway obstruction is higher than the COPD prevalence in the Portuguese population. We recommend stopping smoking and use of equipment for respiratory protection.

Effects of Hardwood Smoke Exposure on Allergic Airway Inflammation in Mice

Hardwood smoke (HWS) from wood burning stoves and fireplaces can be a significant contributor to the composition of ambient air pollution. We hypothesize that the inhalation of HWS by ovalbumin (OVA)-sensitized mice with preexisting lung inflammation leads to the exacerbation of allergic airway responses. Two different models were employed to characterize the effects of inhaled wood smoke on allergic airway inflammation. In both models, male BALB/c mice were sensitized by injection with OVA and alum. In one model, mice were challenged by inhalation with OVA 1 day prior to exposure to HWS (30, 100, 300, or 1000 μg particulate matter [PM]/m3) for 6 h/day on 3 consecutive days. In the other model, mice were exposed by inhalation to OVA, rested for 11 days, were exposed to HWS for 3 consecutive days, and then were exposed to OVA immediately after the final HWS exposure. Bronchoalveolar lavage (BAL), and blood collection were performed ∼ 18 h after the last HWS or OVA exposure. HWS exposure after the final allergen challenge (first model) led to a significant increase in BAL eosinophils only at the 300 μg/m3 level. In contrast, changes in BAL cells did not reach statistical significance in the second model. There were no HWS-induced changes in BAL interleukin (IL)-2, IL-4, IL-13, and interferon (IFN)γ levels in either model following OVA challenge. These results suggest that acute HWS exposure can minimally exacerbate some indices of allergic airway inflammation when a final OVA challenge precedes HWS exposure, but does not alter Th1/Th2 cytokine levels.

Assessment of oxidative stress in lungs from sheep after inhalation of wood smoke.

To elucidate potential dose-dependent mechanisms associated with wood smoke inhalation injury, the present study evaluated antioxidant status and the extent of pulmonary injury in sheep after graded exposure to smoke. Adult, male sheep (n=4-5 per group) were anesthetized and received 0, 5, 10 or 16 units of cooled western pine bark smoke, corresponding to 0, 175, 350 and 560 s, respectively, of smoke dwell time in the airways and lung. Smoke was mixed at a 1:1 ratio with 100% O2 to minimize hypoxia. Plasma and expired breath samples were collected pre-smoke, and 6, 12, 18, 24, 36 and 48 h after smoke exposure. Sheep were euthanatized 48 h after smoke exposure and lung and airway sections were evaluated histologically for injury and biochemically for indices of oxidative stress. Plasma thiobarbituric acid reactive substances (TBARS) were 66 and 69% higher than controls after moderate and severe smoke exposure at 48 h, whereas total antioxidant potential was not statistically different among groups at any time after exposure. Lung TBARS showed a dose-dependent response to smoke inhalation and were approximately 2-, 3- and 4-fold higher, respectively, than controls after exposure to 5, 10 and 16 units of smoke. Lung myeloperoxidase (MPO) activity was also higher in smoke-exposed animals than controls, and MPO activity was markedly elevated (19- and 22-fold higher than controls in right apical and medial lobes) in response to severe smoke exposure. Smoke exposure also induced a dose-dependent injury to tracheobronchial epithelium and lung parenchyma. Taken together these data show that few indices of oxidative stress responded in a dose-dependent manner to graded doses of smoke inhalation, although most of the indices measured in lung were affected by the highest dose of smoke. Additional time course studies are necessary to determine whether these oxidants are a cause or a consequence of the airway and lung injury associated with exposure to wood smoke.

Effects of exogenous surfactant supplementation and partial liquid ventilation on acute lung injury induced by wood smoke inhalation in newborn piglets.

To investigate the beneficial effects of exogenous surfactant supplementation (ESS) and partial liquid ventilation (PLV) in treating acute lung injury induced by wood smoke inhalation. A prospective, randomized, controlled, multigroup study. An animal research laboratory at a medical center. Newborn piglets (n = 29; 1.80 +/- 0.06 kg) of either sex. Animals were ventilated with a tidal volume of 15 mL/kg, a rate of 30 breaths/min, a positive end-expiratory pressure of 5 cm H(2)O, and an Fio(2) of 1.0. After the induction of acute lung injury by wood smoke inhalation, animals were randomly assigned to receive either conventional mechanical ventilation (CMV) or PLV with or without ESS pretreatment. Animals were grouped as CMV, ESS-CMV, PLV, and ESS-PLV. Arterial blood gases, cardiovascular hemodynamics, dynamic lung compliance, and total lung injury scores were measured. After smoke inhalation, all four groups displayed similar high arterial carboxyhemoglobin levels, low Pao(2) (<150 mm Hg), and low dynamic lung compliance (<66% of its baseline). In the CMV group, these deleterious conditions remained during the 4-hr observation period, and severe lung injury was noted histologically. All treatment groups demonstrated a significant increase in Pao(2) compared with the CMV group. In addition, both the PLV and ESS-PLV groups displayed significant improvements in dynamic lung compliance and in their histologic outcomes. Nevertheless, none of the variables measured in the PLV group differed from those measured in the ESS-PLV group. In a newborn piglet model of smoke inhalation injury, PLV or ESS improved oxygenation. PLV compared favorably with ESS in its greater improvements in lung compliance and lung pathology. However, the combined therapy of ESS and PLV was not clearly superior to PLV alone during the observation period.

Indices of antioxidant status in rats subjected to wood smoke inhalation and/or thermal injury

The present study investigated antioxidant status in lavage fluid, lung, liver, heart and kidney in a rat model to simulate an inhalation injury as might be encountered by firefighters and burn victims. Anesthetized rats received either a 20% total body surface area (TBSA) full thickness scald or a sham burn. After a 5 h recovery period, half of the animals in the burn or sham burn groups were exposed to cooled western bark (fir and pine) smoke for 16.25 min. The remaining rats in each group breathed room air. At 1, 12, 24, 48 and 96 h after exposure to the smoke, five rats from each of the four groups were euthanatized and lungs were lavaged by infusing three 5 ml aliquots of normal saline for evaluation of airway cellular content and lung wet to dry weight ratios to estimate lung water content. A second series of five rats/group per time point were euthanatized at the above times and lung, liver, kidney and heart were removed for evaluation of tissue antioxidant enzyme activities and for thiobarbituric acid reactive substances (TBARS) concentrations, as well as for lung histology. Smoke exposure resulted in average plasma carboxyhemoglobin (COHb) of 19±2% in the two smoke exposed groups and produced areas of erosion of the tracheal surface, resulting in loss of epithelium and exposed basement membrane. Lung water content was not significantly different among the four groups during the 96-h experimental period. Lung TBARS levels were 2–3-fold higher at 12 h in smoke exposed rats compared with controls. These levels peaked at 24 h and remained significantly elevated at 48 h compared to controls. TBARS were also elevated in liver, but not in heart or kidney in response to burn or combined injury. Minor effects on lung antioxidant enzyme activities were observed after smoke inhalation. These data suggest that smoke inhalation, independent of burn injury, induces an oxidant stress that persists for at least the first 48 h after smoke exposure.

Alleviation of wood smoke-induced lung injury by tachykinin receptor antagonist and hydroxyl radical scavenger in guinea pigs

We recently reported that wood smoke inhalation initially (within 5 min) causes airway injury and subsequently produces both airway and parenchymal injury after a delay (within 2 h). In this study, we investigated the mediator mechanisms of this delayed smoke-induced lung injury in 126 anesthetized and artificially ventilated guinea pigs who received challenges of either air or 40 tidal breaths of wood smoke. Two hours after inhalation, wood smoke produced various injurious responses, including increases in alveolar–capillary permeability, microvascular permeabilities, and histological injury scores, in airway and parenchymal tissues. Pre-treatment given before smoke challenge with CP-96,345 [a tachykinin NK 1 receptor antagonist; (2 S,3 S)- cis-2-(diphenylmethyl)- N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine], dimethylthiourea (a hydroxyl radical scavenger), or a combination of these two drugs largely alleviated both the airway and parenchymal responses, whereas pre-treatment with SR-48,968 [a tachykinin NK 2 receptor antagonist; ( S)- N-methyl- N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl)benzamide] or a combination of CP-96,344 and SR-48,965 (inactive enantiomers) failed to do so. Post-treatment given at 5 min after smoke challenge with CP-96,345 or dimethylthiourea significantly alleviated the parenchymal responses, while having no effect on the airway responses. Pre-treatment with dimethylthiourea prevented the smoke-induced reduction in airway neutral endopeptidase activity (an enzyme for tachykinin degradation). We concluded that (1) tachykinins and hydroxyl radical play important roles in producing smoke-induced delayed lung injury in guinea pigs, and both may be involved in the spread of injury from the airways to the pulmonary parenchyma, and (2) the contribution of tachykinins is mediated via the activation of tachykinin NK 1 receptors, and is associated with the hydroxyl radical-induced inactivation of airway neutral endopeptidase.

Acute neurogenic airway plasma exudation and edema induced by inhaled wood smoke in guinea pigs: role of tachykinins and hydroxyl radical

We studied the mechanisms underlying the wood smoke-induced acute airway injury in 120 anaesthetized guinea pigs. Five minutes after airway exposure, various doses of wood smoke produced a dose-dependent increase in Evans blue dye contents at all airway levels measured. Additionally, inhaled wood smoke produced submucosal edema of the trachea and bronchus, and peribronchial edema. These acute airway responses were nearly abolished by pretreatment with CP-96,345 alone [a tachykinin NK 1 receptor antagonist; (2 S,3 S)-cis-2-(diphenylmethyl)- N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine] or with a combination of CP-96,345 and dimethylthiourea (a hydroxyl radical scavenger), and were attenuated by pretreatment with dimethylthiourea alone, yet were not affected by pretreatment with SR-48,968 [a tachykinin NK 2 receptor antagonist; ( S)- N-methyl- N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl)benzamide], with a combination of CP-96,344 and SR-48,965 (inactive enantiomers), with MK-886 [a leukotriene biosynthesis inhibitor; L-663,536(3-(1-(4-chlorobenzyl)-3- t-butyl-thio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid], with indomethacin (a cyclooxygenase inhibitor), or with N G-nitro- l-arginine methyl ester (a nitric oxide (NO) synthase inhibitor). The activity of airway neutral endopeptidase (an enzyme for tachykinin degradation) was not influenced by wood smoke at 5-min post-exposure. We conclude that both endogenous tachykinins and hydroxyl radical play an important role in producing smoke-induced acute airway plasma exudation and airway edema in guinea pigs. The contribution of tachykinins to these neurogenic responses is mediated via the activation of tachykinin NK 1 receptors and partly via a hydroxyl radical mechanism, and is not associated with inactivation of neutral endopeptidase.

Wood smoke-induced airway hyperreactivity in guinea pigs: Time course, and role of leukotrienes and hydroxyl radical

A prior airway exposure to wood smoke induces a tachykinin-dependant increase in airway responsiveness to the subsequent smoke inhalation in guinea pigs ( Life Sci. 63: 1513, 1998). To further investigate the time course of, and the contribution of other chemical mediators to, this smoke-induced airway hyperresponsiveness (SIAHR), two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs of anesthetized guinea pigs by a respirator. In the control animals, the SIAHR was evidenced by the bronchoconstrictive response to the second smoke challenge (SM2) which was ~ 5.2-fold greater than that to the first challenge (SM1). This SIAHR was alleviated by shortening the elapsed time between SM1 and SM2 to 10 min or by extending it to 60 min, and was abolished by extending it to 120 min. This SIAHR was reduced by pretreatment with either MK-571 (a leukotriene D 4-receptor antagonist) or dimethylthiourea (a hydroxyl radical scavenger), but was not affected by pretreatment with either pyrilamine (a histamine H 1-receptor antagonist) or indomethacin (a cyclooxygenase inhibitor). The smoke-induced reduction in the neutral endopeptidase activity (a major enzyme for tachykinin degradation) measured in airway tissues excised 30 min post SM1 was largely prevented by pretreatment with dimethylthiourea. However, this reduction was not seen in airway tissues excised 120 min post SM1. These results suggest that 1) the SIAHR to inhaled wood smoke has a rapid onset time following smoke inhalation and lasts for less than two hours, 2) leukotrienes and hydroxyl radical may play contributory roles in the development of this SIAHR, and 3) hydroxyl radical is the major factor responsible for the smoke-induced inactivation of airway neutral endopeptidase, which may possibly participate in the development of this SIAHR.

Neonatal capsaicin treatment alters immediate ventilatory responses to inhaled wood smoke in rats

Neonatal capsaicin treatment chronically ablates unmyelinated C fibers, yet also destroys a small amount of myelinated fibers. Inhalation of wood smoke evokes respiratory reflexes resulting from stimulation of both lung C-fiber nerve endings (unmyelinated afferents) and irritant receptors (myelinated afferents). This study investigated the influences of neonatal capsaicin treatment on the immediate ventilatory responses to inhaled wood smoke in adult rats. Inhalation of wood smoke (∼6 ml) via a tracheostomy immediately triggered only an augmented inspiration in 16 rats neonatally treated with capsaicin (50 mg/kg, subcutaneous injection). In contrast, inhaled wood smoke evoked a slowing of respiration in 11 neonatal vehicle-treated rats and an augmented inspiration in another five. The inability to exhibit the slowing of respiration and the persistence of the augmented inspiration in capsaicin-treated rats are consistent with our hypothesis that these two reflex responses originate from stimulation of lung vagal C-fiber afferents and irritant receptors, respectively. Since all capsaicin-treated rats responded to smoke with an augmented inspiration, it is further suggested that neonatal capsaicin treatment selectively impairs the reflex functions of C-fiber afferents and well preserves the reflex functions of lung irritant receptors.