Severity Of Lung Inflammation Research Articles

Cholesterol-Modified Anti-Il6 siRNA Reduces the Severity of Acute Lung Injury in Mice.

Small interfering RNA (siRNA) holds significant therapeutic potential by silencing target genes through RNA interference. Current clinical applications of siRNA have been primarily limited to liver diseases, while achievements in delivery methods are expanding their applications to various organs, including the lungs. Cholesterol-conjugated siRNA emerges as a promising delivery approach due to its low toxicity and high efficiency. This study focuses on developing a cholesterol-conjugated anti-Il6 siRNA and the evaluation of its potency for the potential treatment of inflammatory diseases using the example of acute lung injury (ALI). The biological activities of different Il6-targeted siRNAs containing chemical modifications were evaluated in J774 cells in vitro. The lead cholesterol-conjugated anti-Il6 siRNA after intranasal instillation demonstrated dose-dependent therapeutic effects in a mouse model of ALI induced by lipopolysaccharide (LPS). The treatment significantly reduced Il6 mRNA levels, inflammatory cell infiltration, and the severity of lung inflammation. IL6 silencing by cholesterol-conjugated siRNA proves to be a promising strategy for treating inflammatory diseases, with potential applications beyond the lungs.

Acute HDM exposure shows time-of-day and sex-based differences in the severity of lung inflammation and circadian clock disruption.

Asthma is a chronic inflammatory disease that shows a time-of-day response to variations in symptoms/severity. However, how the lung circadian clock influences time-of-day response and sex-based differences in house dust mite (HDM)-induced airway inflammation and remodeling has not been thoroughly investigated. We sought to determine whether acute HDM exposure in wild-type mice shows time-of-day response and sex-based differences in allergic airway inflammation and circadian clock disruption in the lungs. Wild-type (C57BL/6J) and Rev-erbα knockout (KO) mice were exposed to either PBS or HDM (for 10 days) intranasally at Zeitgeber time (ZT0: 6 am; ZT12: 6 pm) and euthanized 48 hours after the last exposure. Acute HDM-induced time-of-day response and sex-based differences in lung inflammation, gated cytokines/chemokines, humoral and hormonal responses, and circadian clock gene expression were analyzed. Acute HDM-exposed mice showed a time-of-day response and sex-based differences in exaggerated lung inflammation (inflammatory eosinophils and interstitial macrophages) at ZT12 when compared with ZT0. HDM-exposed female mice showed increased inflammatory response at ZT12, but HDM-exposed male mice showed comparatively lower inflammation with no time-of-day response. HDM-exposed female and male mice showed augmented IgE levels at ZT12 when compared with ZT0. Myeloid innate immunity panel, cytokines/chemokines, and mucin genes showed a time-of-day gating response at ZT0 and ZT12 in the HDM group. In addition, HDM exposure altered the expression of circadian clock genes in the lung, which was evident in female mice at ZT12. Overall, female mice showed significant time-of-day responses to all these parameters compared with male mice. Rev-erbα KO mice exposed to acute HDM showed exaggerated lung inflammation associated with increased IgE and proinflammatory cytokines in bronchoalveolar lavage fluid. Interestingly, HDM exposure causes reduced expression of clock genes in flow-sorted resident eosinophils but not alveolar macrophages. Acute HDM exposure reduced the nocturnal locomotor activity in mice 5 days post-HDM exposure until day10. This study shows a time-of-day response to acute HDM exposure and sex-based differences in the severity of lung inflammation and humoral immune response associated with circadian clock disruption. Our findings support the use of separate female and male mice cohorts for preclinical studies to understand the molecular heterogeneity in asthma pathophysiology.

Regulation of von Willebrand factor by ADAMTS13 ameliorates lipopolysaccharide-induced lung injury in mice.

The relationship between von Willebrand factor (VWF) and inflammation has attracted considerable attention in recent years. VWF, which is stored in the Weibel-Palade bodies (WPBs) of endothelial cells (ECs), is released from WPBs in response to inflammatory stimuli and is thought to contribute to inflammation by promoting leukocyte extravasation. In this study, lung injury model mice were produced by intratracheal injection with lipopolysaccharides. The severity of lung inflammation was evaluated in mice with different genotypes (wild-type, Vwf-/-, Adamts13-/-) and mice treated with drugs that inhibit VWF function. Lung inflammation was significantly ameliorated in Vwf-/- mice compared with wild-type mice. Furthermore, inflammation was significantly suppressed in wild-type mice treated with anti-VWF A1 antibody or recombinant human ADAMTS13 compared with the untreated control group. The underlying mechanism appears to be an increased VWF/ADAMTS13 ratio at the site of inflammation and the interaction between blood cell components, such as leukocytes and platelets, and the VWF A1 domain, which promotes leukocyte infiltration into the lung. This study suggested that ADAMTS13 protein and other VWF-targeting agents may be a novel therapeutic option for treatment of pulmonary inflammatory diseases.

Regulatory roles of Osteopontin in lung epithelial inflammation and epithelial-telocyte interaction.

Lung epithelial cells play important roles in lung inflammation and injury, although mechanisms remain unclear. Osteopontin (OPN) has essential roles in epithelial damage and repair and in lung cancer biological behaviours. Telocyte (TC) is a type of interstitial cell that interacts with epithelial cells to alleviate acute inflammation and lung injury. The present studies aim at exploring potential mechanisms by which OPN regulates the epithelial origin lung inflammation and the interaction of epithelial cells with TCs in acute and chronic lung injury. The lung disease specificity of OPN and epithelial inflammation were defined by bioinformatics. We evaluated the regulatory roles of OPN in OPN-knockdown or over-expressed bronchial epithelia (HBEs) challenged with cigarette smoke extracts (CSE) or in animals with genome OPN knockout (gKO) or lung conditional OPN knockout (cKO). Acute lung injury and chronic obstructive pulmonary disease (COPD) were induced by smoking or lipopolysaccharide (LPS). Effects of OPN on PI3K subunits and ERK were assessed using the inhibitors. Spatialization and distribution of OPN, OPN-positive epithelial subtypes, and TCs were defined by spatial transcriptomics. The interaction between HBEs and TCs was assayed by the co-culture system. Levels of OPN expression increased in smokers, smokers with COPD, and smokers with COPD and lung cancer, as compared with healthy nonsmokers. LPS and/or CSE induced over-production of cytokines from HBEs, dependent upon the dysfunction of OPN. The severity of lung inflammation and injury was significantly lower in OPN-gKO or OPN-cKO mice. HBEs transferred with OPN enhanced the expression of phosphoinositide 3-kinase (PI3K)CA/p110α, PIK3CB/p110β, PIK3CD/p110δ, PIK3CG/p110γ, PIK3R1, PIK3R2 or PIK3R3. Spatial locations of OPN and OPN-positive epithelial subtypes showed the tight contact of airway epithelia and TCs. Epithelial OPN regulated the epithelial communication with TCs, and the down-regulation of OPN induced more alterations in transcriptomic profiles than the up-regulation. Our data evidenced that OPN regulated lung epithelial inflammation, injury, and cell communication between epithelium and TCs in acute and chronic lung injury. The conditional control of lung epithelial OPN may be an alternative for preventing and treating epithelial-origin lung inflammation and injury.

2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography to Monitor Lung Inflammation and Therapeutic Response to Dexamethasone in a Murine Model of Acute Lung Injury.

To image inflammation and monitor therapeutic response to anti-inflammatory intervention using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) in a preclinical model of acute lung injury (ALI). Mice were intratracheally administered lipopolysaccharide (LPS, 2.5mg/kg) to induce ALI or phosphate-buffered saline as the vehicle control. A subset of mice in the ALI group received two intraperitoneal doses of dexamethasone 1 and 24h after LPS. [18F]FDG PET/CT was performed 2days after the induction of ALI. [18F]FDG uptake in the lungs was quantified by PET (%ID/mLmean and standardized uptake value (SUVmean)) and ex vivo γ-counting (%ID/g). The severity of lung inflammation was determined by quantifying the protein level of inflammatory cytokines/chemokines and the activity of neutrophil elastase and glycolytic enzymes. In separate groups of mice, flow cytometry was performed to estimate the contribution of individual immune cell types to the total pulmonary inflammatory cell burden under different treatment conditions. Lung uptake of [18F]FDG was significantly increased during LPS-induced ALI, and a decreased [18F]FDG uptake was observed following dexamethasone treatment to an intermediate level between that of LPS-treated and control mice. Protein expression of inflammatory biomarkers and the activity of neutrophil elastase and glycolytic enzymes were increased in the lungs of LPS-treated mice versus those of control mice, and correlated with [18F]FDG uptake. Furthermore, dexamethasone-induced decreases in cytokine/chemokine protein levels and enzyme activities correlated with [18F]FDG uptake. Neutrophils were the most abundant cells in LPS-induced ALI, and the pattern of total cell burden during ALI with or without dexamethasone therapy mirrored that of [18F]FDG uptake. [18F]FDG PET noninvasively detects lung inflammation in ALI and its response to anti-inflammatory therapy in a preclinical model. However, high [18F]FDG uptake by bone, brown fat, and myocardium remains a technical limitation for quantification of [18F]FDG in the lungs.

MascRNA alleviates STING-TBK1 signaling-mediated immune response through promoting ubiquitination of STING

mascRNA (MALAT1-associated small cytoplasmic RNA) is a tRNA-like cytoplasmic small noncoding RNA whose function remains elusive. We previously revealed that this small RNA negatively regulates TLR4/2-triggered proinflammatory response while positively regulates TLR3-induced antiviral response. Here, we investigated whether and how mascRNA influences the stimulator of interferon genes (STING) signaling-triggered immune response. We found that overexpression of mascRNA inhibited the expression of type I interferon (IFN) genes and proinflammatory cytokines in response to cytosolic DNA stimulation; meanwhile, the abundance of STING protein and the level of phosphorylated TBK1 and STAT1 was decreased. By contrast, depletion of mascRNA potentiated the expression of type I IFNs, increased STING protein abundance, and promoted STING-mediated phosphorylation of TBK1 and STAT1 in response to DNA stimulation. In a mouse model of DNA-induced lung injury, exogenous mascRNA mitigated the antiviral response and the severity of lung inflammation. Mechanically, mascRNA was found to promote STING for K48-linked ubiquitination and degradation in macrophages both with and without cytosolic DNA stimulation. Hence, mascRNA suppresses STING-TBK1 signaling-mediated innate immunity through promoting proteasomal degradation of STING, and this tRNA-like small RNA holds promise for the treatment of certain inflammatory diseases such as COVID-19 where aberrant STING signaling drives type I IFN immunopathology.

Effects of crocin on T-bet/GATA-3 ratio, and miR-146a and miR-106a expression levels in lung tissue of ovalbumin-sensitized mice.

Objective(s):Although various studies have revealed the beneficial effects of crocin (derived from saffron), such as anti-inflammatory, anti-cancer, antioxidant, and immune modulator, however, its exact mechanism is unknown. The present study aimed to investigate the effect of crocin on the expression ratio of T-bet/GATA-3 as an indicator of altered immune responses in the lung tissue of ovalbumin (OVA)-sensitized mice. In addition, the effect of crocin on the expression level of miR-146a and miR-106a in the lung tissue OVA-sensitized mice was investigated.Materials and Methods:Mice were randomly divided into five groups (n=6): Control; OVA, OVA + Crocin 25, OVA + Cro 50, and OVA + Cro100 groups. Crocin was administrated intraperitoneally at doses of 25, 50, and 100 mg/kg for five consecutive days. One day after asthma induction, animals were euthanized, and lungs were sampled for pathological and gene expression analysis.Results: OVA-sensitization led to increased inflammation and histopathological changes in the lung tissue of mice. In addition, GATA-3 expression increased (P<0.001) and T-bet expression decreased (P<0.001) in OVA-sensitized groups. The T-bet/GATA3 ratio was also reduced markedly in asthma groups (P<0.001). Furthermore, increased expression of miR-146a and miR-106a levels was evident in the lung tissue of OVA-sensitized mice (P<0.001 for both). Intervention with high concentrations of crocin (50 and 100 mg/kg) significantly reduced airway inflammation, GATA-3 expression, miR-146a expression, and miR-106a expression and corrected the T-bet/GATA-3 ratio (P<0.05 to P<0.001).Conclusion:Treatment with crocin led to a decrease in the severity of lung inflammation in OVA-sensitized mice, which is probably through the reduction of the T-bet/GATA-3 ratio, and mir-146a and mir-106a expression level.

Delicate regulation of IL-1β-mediated inflammation by cyclophilin A.

The inflammatory response is tightly regulated, but its regulatory principles are still incompletely understood. Cyclophilin A (CypA) has long been considered as a pro-inflammatory factor. Here, we discover how CypA precisely regulates interleukin-1β (IL-1β)-mediated inflammatory responses. In lipopolysaccharide-treated mice, CypA deficiency initially inhibits and then promotes lung inflammation, which is closely related to IL-1β production. Mechanistically, CypA not only facilitates pro-IL-1β processing by increasing Smurf1-mediated K63-linked ubiquitination in an ATP-dependent manner but also accelerates pro-IL-1β degradation, depending on Smurf1-mediated K48-linked ubiquitination. Moreover, in IL-1β-treated mice, CypA exacerbates lung injury by enhancing cytokine production. It also upregulates the ILK/AKT pathway by inhibiting Cyld-mediated K63-linked ILK deubiquitination, which promotes the epithelial-mesenchymal transition (EMT) to facilitate lung repair. Collectively, CypA promotes inflammation activation by increasing IL-1β production and then promotes inflammation resolution by enhancing redundant pro-IL-1β degradation and IL-1β-induced EMT, indicating the complex and delicate regulation of inflammatory response.

Exacerbation of Mycobacterium avium pulmonary infection by comorbid allergic asthma is associated with diminished mycobacterium-specific Th17 responses

ABSTRACT Accumulating evidence suggests that two chronic respiratory diseases, nontuberculous mycobacterium (NTM)-pulmonary disease (PD) and allergic asthma, are frequently present together and that they likely influence the disease development and progression of each other. However, their precise interactions regarding the pathogenesis of comorbid diseases versus that of individual diseases are not well understood. In this study, comorbid diseases (i.e., Mycobacteria avium (Mav) pulmonary infection (PI) (Mav-PI) and ovalbumin-induced allergic asthma) were established in mice in different orders and at different time periods. Individual disease-specific characteristics, including alterations in immune cell populations and antigen-specific immune responses, were analyzed and compared. To assess Mav-PI pathogenesis, lung inflammation and bacterial burden levels were also determined. Allergic asthma induction in the presence of Mav-PI markedly aggravated Mav-PI pathogenesis by increasing the bacterial burden and the severity of lung inflammation. Interestingly, the general outcome of allergic asthma with goblet cell hyperplasia was alleviated at a chronic stage in the comorbid mouse model. Overall, the increase in the number of Mav CFUs was inversely correlated with the Mav-specific Th17 response, as confirmed by comparing BALB/c and C57BL/6J mice. Overall, the pathogenesis of existing Mav-PI is more severely affected by allergen exposure than vice versa. This Mav-PI exacerbation is associated with disruption of Mav-specific Th17 responses. This study provides the first evidence that the Mav-specific Th17 response plays an important role in the control of Mav pathogenesis in the presence of allergic asthma, indicating that targeting the Th17 response has therapeutic potential for NTM-PD accompanied by allergic asthma.

Dexamethasone Ameliorates Severe Pneumonia But Slightly Enhances Viral Replication in Lung of SARS-CoV-2-Infected Syrian Hamster

Background: The pandemic of SARS-CoV-2 has turned into a global public health crisis. Acute SARS-CoV-2 infection is associated with severe pneumonia, multiple-organ failures and deaths. Currently, treatment for SARS-CoV-2 infection and severe pneumonia is largely lacking. Several clinical trials demonstrated that glucocorticoid dexamethasone is effective to reduce disease severity and mortality. However, whether dexamethasone is clinically sufficient to treat COVID-19 is unknown.Methods: We tested the therapeutic effect of dexamethasone on SARS-CoV-2 infection and pneumonia in a Syrian hamster model. Survival rate, body weight loss, viral RNA, antibody responses, severity of lung inflammation and injury were measured in a 7-day acute infection course.Findings: Dexamethasone reduces body weight loss and relieves the diffusion of lung injury in SARS-CoV-2-infected hamster by inhibiting the excessive proinflammatory cytokines including IL-4, IL-6, IL-10, IL-13, TNF-α and IFN-γ. Dexamethasone rescues hamsters from the lethal infection of SARS-CoV-2 variant D614G. Dexamethasone attenuates serum neutralizing antibody and RBD-specific antibody titers, and slightly increases viral RNA level in lung tissues.Interpretation: Overall, using the hamster model, this study improves our understanding of the therapeutic mechanisms and drawbacks of dexamethasone treatment of COVID-19, and suggests that an antiviral is needed to accompany the dexamethasone treatment regimen.Funding: National Science Key Research and Development Project of China, National Natural Science Foundation of China, the CAMS Innovation Fund for Medical Sciences and China Postdoctoral Science Foundation.Declaration of Interest: The authors declare no competing interests.Ethical Approval: All the animal experiments were approved by the Medical Ethics Committee(SUCM2021-112).

Molecular Imaging of Very Late Antigen-4 in Acute Lung Injury.

Inflammation plays a central role in the pathogenesis of acute lung injury (ALI) during both the acute pneumonitis stage and progression into the chronic fibroproliferative phase, leading to pulmonary fibrosis. Currently, there is an unmet clinical and research need for noninvasive ways to monitor lung inflammation through targeting of immunoregulatory pathways contributing to ALI pathogenesis. In this study, we evaluated the role of targeted imaging of very late antigen-4 (VLA-4), as a key integrin mediating the adhesion and recruitment of immune cells to inflamed tissues, in quantifying lung inflammation in a mouse model of lipopolysaccharide-induced ALI. Methods: ALI was induced by a single intratracheal administration of lipopolysaccharide (10, 20, or 40 μg per mouse) in C57BL/6J mice. Control mice were intratracheally instilled with sterile phosphate-buffered saline. VLA-4-targeted PET/CT was performed 24 h after intravenous injection of a 64Cu-labeled high-affinity peptidomimetic ligand referred to as 64Cu-LLP2A, which is conjugated with the chelator (1,4,8,11-tetraazacyclotetradecane-1-(methane phosphonic acid)-8-(methane carboxylic acid) and a polyethylene glycol 4 linker, at day 2 after the induction of ALI. Ex vivo biodistribution of 64Cu-LLP2A was determined by γ-counting of harvested organs. The severity of lung inflammation was assessed histologically and by measuring the expression of inflammatory markers in the lung tissue lysates using reverse transcription quantitative polymerase chain reaction. Results: Intratracheal lipopolysaccharide instillation led to an acute inflammatory response in the lungs, characterized by increased expression of multiple inflammatory markers and infiltration of myeloid cells, along with a significant and specific increase in 64Cu-LLP2A uptake, predominantly in a peribronchial distribution. There was a strong correlation between the lipopolysaccharide dose and 64Cu-LLP2A uptake, as quantified by in vivo PET (R = 0.69, P < 0.01). Expression levels of both subunits of VLA-4, that is, integrins α4 and β1, significantly correlated with the expression of multiple inflammatory markers, including tumor necrosis factor-α, interleukin-1β, and nitric oxide synthase-2, highlighting the potential of VLA-4 as a surrogate marker of acute lung inflammation. Notably, in vivo 64Cu-LLP2A uptake significantly correlated with the expression of multiple inflammatory markers and VLA-4. Conclusion: Our study demonstrates the feasibility of molecular imaging of VLA-4, as a mechanistically relevant target in ALI, and the accuracy of VLA-4-targeted PET in quantification of ongoing lung inflammation in a murine model.

Intravenous superoxide dismutase as a protective agent to prevent impairment of lung function induced by high tidal volume ventilation

BackgroundPositive-pressure mechanical ventilation is essential in assisting patients with respiratory failure in the intensive care unit and facilitating oxygenation in the operating room. However, it was also recognized as a primary factor leading to hospital-acquired pulmonary dysfunction, in which pulmonary oxidative stress and lung inflammation had been known to play important roles. Cu/Zn superoxide dismutase (SOD) is an important antioxidant, and possesses anti-inflammatory capacity. In this study, we aimed to study the efficacy of Cu/Zn SOD, administered intravenously during high tidal volume (HTV) ventilation, to prevent impairment of lung function.MethodsThirty-eight male Sprague-Dawley rats were divided into 3 groups: 5 h ventilation with (A) low tidal volume (LTV; 8 mL/kg; n = 10), (B) high tidal volume (HTV; 18 mL/kg; n = 14), or (C) HTV and intravenous treatment of Cu/Zn SOD at a dose of 1000 U/kg/h (HTV + SOD; n = 14). Lung function was evaluated both at baseline and after 5-h ventilation. Lung injury was assessed by histological examination, lung water and protein contents in the bronchoalveolar lavage fluid (BALF). Pulmonary oxidative stress was examined by concentrations of methylguanidine (MG) and malondialdehyde (MDA) in BALF, and antioxidative activity by protein expression of glutathione peroxidase-1 (GPx-1) in the lung. Severity of lung inflammation was evaluated by white blood cell and differential count in BALF, and protein expression of inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), and mRNA expression of nuclear factor-κB (NF-κB) in the lung. We also examined protein expression of surfactant protein (SP)-A and D and we measured hourly changes in serum nitric oxide (NO) level.ResultsFive hours of LTV ventilation did not induce a major change in lung function, whereas 5 h of HTV ventilation induced apparent combined restrictive and obstructive lung disorder, together with increased pulmonary oxidative stress, decreased anti-oxidative activity and increased lung inflammation (P < 0.05). HTV ventilation also decreased SP-A and SP-D expression and suppressed serum NO level during the time course of ventilation. Cu/Zn SOD administered intravenously during HTV ventilation effectively reversed associated pulmonary oxidative stress and lung inflammation (P < 0.05); moreover, it preserved SP-A and SP-D expressions in the lung and increased serum nitric oxide (NO) level, enhancing vascular NO bioavailability.ConclusionsHTV ventilation can induce combined restrictive and obstructive lung disorders. Intravenous administration of Cu/Zn SOD during HTV ventilation can prevent lung function impairment and lung injury via reducing pulmonary oxidative stress and lung inflammation, preserving pulmonary surfactant expression, and enhancing vascular NO bioavailability.

Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses.

Titanium dioxide nanoparticles (TiO2NPs) induce lung inflammation in experimental animals. In this study, we conducted a comprehensive toxicogenomic analysis of lung responses in mice exposed to six individual TiO2NPs exhibiting different sizes (8, 20 and 300nm), crystalline structure (anatase, rutile or anatase/rutile) and surface modifications (hydrophobic or hydrophilic) to investigate whether the mechanisms leading to TiO2NP-induced lung inflammation are property specific. A detailed histopathological analysis was conducted to investigate the long-term disease implications of acute exposure to TiO2NPs. C57BL/6 mice were exposed to 18, 54, 162 or 486 µg of TiO2NPs/mouse via single intratracheal instillation. Controls were exposed to dispersion medium only. Bronchoalveolar lavage fluid (BALF) and lung tissue were sampled on 1, 28 and 90 days post-exposure. Although all TiO2NPs induced lung inflammation as measured by the neutrophil influx in BALF, rutile-type TiO2NPs induced higher inflammation with the hydrophilic rutile TiO2NP showing the maximum increase. Accordingly, the rutile TiO2NPs induced higher number of differentially expressed genes. Histopathological analysis of lung sections on Day 90 post-exposure showed increased collagen staining and fibrosis-like changes following exposure to the rutile TiO2NPs at the highest dose tested. Among the anatase, the smallest TiO2NP of 8nm showed the maximum response. The anatase TiO2NP of 300nm was the least responsive of all. The results suggest that the severity of lung inflammation is property specific; however, the underlying mechanisms (genes and pathways perturbed) leading to inflammation were the same for all particle types. While the particle size clearly influenced the overall acute lung responses, a combination of small size, crystalline structure and hydrophilic surface contributed to the long-term pathological effects observed at the highest dose (486 µg/mouse). Although the dose at which the pathological changes were observed is considered physiologically high, the study highlights the disease potential of certain TiO2NPs of specific properties.

Inhibition of mTOR Increases the Severity of Lung Inflammation in Mice Infected With Influenza A Virus

Inhibition of mTOR Increases the Severity of Lung Inflammation in Mice Infected With Influenza A Virus

Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury.

Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4°C for 8h each day for 14days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma--a review.

Multiple trauma patients require extremely good management and thus, the trauma team needs to be prepared and to be up to date with the new standards of intensive therapy. Oxidative stress and free radicals represent an extremely aggressive factor to cells, having a direct consequence upon the severity of lung inflammation. Pulmonary tissue is damaged by oxidative stress, leading to biosynthesis of mediators that exacerbate inflammation modulators. The subsequent inflammation spreads throughout the body, leading most of the time to multiple organ dysfunction and death. In this paper, we briefly present an update of biochemical effects of oxidative stress and free radical damage to the pulmonary tissue in patients in critical condition in the intensive care unit. Also, we would like to present a series of active substances that substantially reduce the aggressiveness of free radicals, increasing the chances of survival.

FDG PET Imaging in Cystic Fibrosis

Cystic fibrosis (CF) is characterized by persistent neutrophilic lung inflammation that begins early in life and leads to an inexorable progressive loss of lung function over time, causing significant morbidity and mortality. Studies to date support the hypothesis that higher levels of lung inflammation lead to worsening lung dysfunction. However, measuring the extent and severity of lung inflammation in the CF lung is difficult as few lung-specific biomarkers of inflammation can quantify the regional and whole-lung inflammatory burden accurately and reproducibly. PET with (18)F-fluorodeoxyglucose ((18)F-FDG) has shown promise in measuring lung inflammation in both acute and chronic lung diseases. Several studies have now shown that (18)F-FDG uptake may be a useful measure of lung inflammation in CF. The whole-lung rate of (18)F-FDG uptake in stable CF, quantified by the Patlak graphical analysis, appears to correlate with more rapidly declining lung function. Acute exacerbation, on the contrary, leads to focally increased (18)F-FDG uptake, which decreases with antibiotic treatment. These small studies are the first attempts to characterize the patterns of (18)F-FDG uptake in CF and suggest a potential role for (18)F-FDG as a treatment modifiable biomarker of lung inflammation in CF.

Primary Severe Acute Respiratory Syndrome Coronavirus Infection Limits Replication but Not Lung Inflammation upon Homologous Rechallenge

Our knowledge regarding immune-protective and immunopathogenic events in severe acute respiratory syndrome coronavirus (SARS-CoV) infection is limited, and little is known about the dynamics of the immune response at the primary site of disease. Here, an African green monkey (AGM) model was used to elucidate immune mechanisms that facilitate viral clearance but may also contribute to persistent lung inflammation following SARS-CoV infection. During primary infection, SARS-CoV replicated in the AGM lung for up to 10 days. Interestingly, lung inflammation was more prevalent following viral clearance, as leukocyte numbers peaked at 14 days postinfection (dpi) and remained elevated at 28 dpi compared to those of mock-infected controls. Lung macrophages but not dendritic cells were rapidly activated, and both cell types had high activation marker expression at late infection time points. Lung proinflammatory cytokines were induced at 1 to 14 dpi, but most returned to baseline by 28 dpi except interleukin 12 (IL-12) and gamma interferon. In SARS-CoV homologous rechallenge studies, 11 of the 12 animals were free of replicating virus at day 5 after rechallenge. However, incidence and severity of lung inflammation was not reduced despite the limited viral replication upon rechallenge. Evaluating the role of antibodies in immune protection or potentiation revealed a progressive increase in anti-SARS-CoV antibodies in lung and serum that did not correlate temporally or spatially with enhanced viral replication. This study represents one of the first comprehensive analyses of lung immunity, including changes in leukocyte populations, lung-specific cytokines, and antibody responses following SARS-CoV rechallenge in AGMs.

Monitoring Treatment Responses in Patients with Pulmonary TB Using Serial Lung Gallium-67 Scintigraphy

Gallium-67 scintigraphy is more sensitive than chest radiography in a single concurrent detection of pulmonary tuberculosis (TB). As for inflammation, the intensity of pulmonary uptake of 67Ga citrate theoretically is a function of the inflammation level in the lung. To maximize clinical applicability of 67Ga scintigraphy in the evaluation of pulmonary TB, we prospectively assessed serial qualitative associations between intensity of the uptake of 67Ga citrate and the severity of lung inflammation, reflected by the burden of Mycobacterium tuberculosis in the sputum of patients undergoing anti-TB chemotherapy. Each enrolled patient had chest radiographic, microbiologic, 67Ga imaging, and semiquantitation of sputum acid-fast bacillus (AFB) assessments before and at the third and sixth months after receiving anti-TB chemotherapy. The burden of pulmonary M. tuberculosis (presumably, in proportion to the semiquantitation of AFB in sputum) and the intensity of 67Ga citrate uptake in the lung at each synchronized assessment were regarded as a paired variable. Odds ratios were obtained from odds (derived using generalized estimating equations) in favor of higher pulmonary 67Ga uptake in differing scores of semiquantitation of sputum AFB. Linear trend for pulmonary 67Ga citrate uptake corresponding to varied pulmonary M. tuberculosis burdens was assessed using contrast analysis of their odds ratios. Thirty patients (24 men and six women) with pulmonary TB were enrolled. Eighty-six paired semiquantitations of sputum AFB-67Ga-scintigraphic studies were collected. Twenty-six patients were cured of their pulmonary TB. The pulmonary 67Ga uptake increased in proportion to the higher score of semiquantitation of sputum AFB (p = 0.009, for trend). In patients with pulmonary TB, the higher the burden of M. tuberculosis in the lung, the higher the intensity of pulmonary 67Ga citrate uptake. Serial 67Ga-scintigraphy examinations are helpful in evaluations of the effectiveness of anti-TB therapy when assessments based on chest radiography are difficult.

CD59a deficiency exacerbates influenza-induced lung inflammation through complement-dependent and -independent mechanisms.

Influenza-specific immune activity not only promotes virus clearance but also causes immunopathology, thereby underlining the importance of mounting a measured anti-viral immune response. Since complement bridges both the innate and adaptive immune systems and has been implicated in defence against influenza, the role of the complement regulator CD59a in modulating the response to influenza was explored. For this purpose, immune responses to influenza virus, strain E61-13-H17, in mice deficient in the complement regulator protein CD59a (Cd59a–/– mice) were compared to those in wild-type mice. The severity of lung inflammation was significantly enhanced in the lungs of Cd59a–/– mice with increased numbers of infiltrating neutrophils and CD4+ T cells. When complement was inhibited using soluble complement receptor1, the frequency of lung-infiltrating neutrophils in influenza-infected Cd59a–/– mice was much reduced whilst numbers of CD4+ T cells remained unchanged. These results demonstrate that CD59a, previously defined as a complement regulator, modulates both the innate and adaptive immune response to influenza virus by both complement-dependent and-independent mechanisms.