Factor In Lung Injury Research Articles

Respiratory Rate as a Factor in Lung Injury-Not Just What You Set, but How You Set.

Respiratory Rate as a Factor in Lung Injury-Not Just What You Set, but How You Set.

The effects of BMMSC treatment on lung tissue degeneration in elderly macaques

BackgroundAge-associated lung tissue degeneration is a risk factor for lung injury and exacerbated lung disease. It is also the main risk factor for chronic lung diseases (such as COPD, idiopathic pulmonary fibrosis, cancer, among others). So, it is particularly important to find new anti-aging treatments.MethodsWe systematically screened and evaluated elderly senile multiple organ dysfunction macaque models to determine whether BMMSCs inhibited lung tissue degeneration.ResultsThe average alveolar area, mean linear intercept (MLI), and fibrosis area in the elderly macaque models were significantly larger than in young rhesus monkeys (p < 0.05), while the capillary density around the alveoli was significantly low than in young macaque models (p < 0.05). Intravenous infusion of BMMSCs reduced the degree of pulmonary fibrosis, increased the density of capillaries around the alveoli (p < 0.05), and the number of type II alveolar epithelium in elderly macaques (p < 0.05). In addition, the infusion reduced lung tissue ROS levels, systemic and lung tissue inflammatory levels, and Treg cell ratio in elderly macaque models (p < 0.05). Indirect co-cultivation revealed that BMMSCs suppressed the expression of senescence-associated genes, ROS levels, apoptosis rate of aging type II alveolar epithelial cells (A549 cells), and enhanced their proliferation (p < 0.05).ConclusionsBMMSC treatment inhibited age-associated lung tissue degeneration.

HIP/PAP protects against bleomycin-induced lung injury and inflammation and subsequent fibrosis in mice.

Hepatocarcinoma‐intestine‐pancreas/pancreatitis‐associated protein (HIP/PAP), a C‐type lectin, exerts anti‐oxidative, anti‐inflammatory, bactericidal, anti‐apoptotic, and mitogenic functions in several cell types and tissues. In this study, we explored the role of HIP/PAP in pulmonary fibrosis (PF). Expression of HIP/PAP and its murine counterpart, Reg3B, was markedly increased in fibrotic human and mouse lung tissues. Adenovirus‐mediated HIP/PAP expression markedly alleviated bleomycin (BLM)‐induced lung injury, inflammation, and fibrosis in mice. Adenovirus‐mediated HIP/PAP expression alleviated oxidative injury and lessened the decrease in pulmonary superoxide dismutase (SOD) activity in BLM‐treated mice, increased pulmonary SOD expression in normal mice, and HIP/PAP upregulated SOD expression in cultured human alveolar epithelial cells (A549) and human lung fibroblasts (HLF‐1). Moreover, in vitro experiments showed that HIP/PAP suppressed the growth of HLF‐1 and ameliorated the H2O2‐induced apoptosis of human alveolar epithelial cells (A549 and HPAEpiC) and human pulmonary microvascular endothelial cells (HPMVEC). In HLF‐1, A549, HPAEpiC, and HPMVEC cells, HIP/PAP did not affect the basal levels, but alleviated the TGF‐β1‐induced down‐regulation of the epithelial/endothelial markers E‐cadherin and vE‐cadherin and the over‐expression of mesenchymal markers, such as α‐SMA and vimentin. In conclusion, HIP/PAP was found to serve as a potent protective factor in lung injury, inflammation, and fibrosis by attenuating oxidative injury, promoting the regeneration of alveolar epithelial cells, and antagonizing the pro‐fibrotic actions of the TGF‐β1/Smad signaling pathway.

Abstract 13929: Pulmonary Artery Diameter Index Predicts the Complications of Balloon Pulmonary Angioplasty

Backgrounds: Balloon pulmonary angioplasty (BPA) has been an attractive strategy as a new treatment for peripheral type chronic thromboembolic pulmonary hypertension (CTEPH). However, BPA occasionally causes fatal complications such as hemorrhagic pulmonary edema, and asymptomatic mild lung injury detected on computed tomography (CT) image is not rare. Pathogenesis of lung injury after BPA has been considered to be a direct vascular injury due to guide wire or balloon, cytokine release at the time of reperfusion, and vulnerability of peripheral pulmonary vascular wall. However, predictive factors of lung injury have not been established. The pulmonary artery expansion of the central portion is frequently observed in patients with advanced pulmonary hypertension and the pulmonary artery diameter can be measured easily and accurately by CT. Therefore, we focused on the pulmonary artery diameter and investigated the association between complications after BPA. Methods: The subject consisted of 16 CTEPH patients diagnosed by right heart catheterization and pulmonary arteriography who underwent BPA (2 males, 14 females, age 60.5 ± 11 years. Initial hemodynamic indices of study subjects were mean pulmonary artery pressure (mPAP) 48.8±12.8 mmHg, cardiac output (CO) 3.62±1.07 L/min, and pulmonary vascular resistance (PVR) 11.6±8.15 WoodUnits. Patients were divided into two groups: group N (no symptoms or signs of any complications, n=9) and group C (symptoms such as hemoptysis or lung infiltration on CT image without symptoms, n=7). We measured pulmonary artery diameter on CT at the transition from the main trunk to the right pulmonary artery and corrected by body surface area. We defined this as the pulmonary diameter index. Results: CO was lower in group C than in group N, but there was no difference in mPAP, PVR, BNP, and the use of pulmonary vasodilators between two groups. Pulmonary artery diameter index in group C was significantly higher than that in group N (21.95 ± 5.89 vs. 14.22 ± 2.41 mm/m 2 , P&lt;0.01). ROC curve indicated 85.7% sensitivity and 88.9% specificity using cut-off value of 18.0 to predict the complications after BPA. Conclusions: Our study suggested that pulmonary artery diameter index would be a novel predictor of the complications after BPA.

Visualization of Fra-1/AP-1 activation during LPS-induced inflammatory lung injury using fluorescence optical imaging.

Inappropriate lung inflammatory response following oxidant and toxicant exposure can lead to abnormal repair and disease pathogenesis, including fibrosis. Thus early detection of molecular and cellular processes and mediators promoting lung inflammation is necessary to develop better strategies for therapeutic intervention and disease management. Previously, we have shown that transcription factor Fra-1/AP-1 plays key roles in lung inflammatory response, as Fra-1-null mice are less susceptible than wild-type mice to LPS-induced lung injury and mortality. Herein, we developed a transgenic reporter mouse model expressing tdTomato under the control of FRA-1 (human) promoter (referred to as FRA-1(TdTg) mice) to monitor its activation during inflammatory lung injury using fluorescence protein-based optical imaging and molecular analysis in vivo and ex vivo. A higher red fluorescent signal was observed in the lungs of LPS-treated FRA-1(TdTg) mice compared with vehicle controls, and Western blot and qRT-PCR analyses revealed a significant correlation with the FRA-1-tdTomato reporter expression. Immunocolocalization demonstrated expression of FRA-1-tdTomato largely in lung alveolar macrophages and to some extent in epithelial cells. Moreover, we validated these results with a second reporter mouse model that expressed green fluorescent protein upon activation of endogenous Fra-1 promoter. Additionally, we demonstrated increased expression of FRA-1 in alveolar macrophages in human lung instilled with Escherichia coli ex vivo. Collectively, our data obtained from two independent reporter mouse models and from human samples underscore the significance of Fra-1 activation in alveolar macrophages during inflammatory lung injury and may aid in developing strategies to target this transcription factor in lung injury and repair.

Interferon-induced helicase (IFIH1) polymorphism with systemic lupus erythematosus and dermatomyositis/polymyositis

The aim of the present study was to evaluate whether the interferon-induced helicase (IFIH1) Ala946Thr (rs1990760 A>G) polymorphism is associated with susceptibility to systemic lupus erythematosus (SLE) and dermatomyositis (DM) or polymyositis (PM) in the Japanese population. The study population consisted of 243 SLE patients, 125 DM/PM patients, and 268 healthy controls from Japan. A Taqman single nucleotide polymorphism genotyping assay was designed for rs1990760 by Applied Biosystems. There were no significant differences between SLE and DM/PM patients and healthy controls regarding the frequency of each genotype and allele. However, the frequency of the AA genotype and the A allele tended to be higher in PM patients with interstitial lung disease (ILD). Additionally, when comparing the AA and AG + GG genotypes at rs1990760, the AA genotype was significantly more frequent in PM patients with ILD than in healthy controls [odds ratio, 3.23 (95% confidence interval, 1.06–9.81); P = 0.04] or in PM patients without ILD [odds ratio, 5.40 (95% confidence interval, 1.37–21.26); P = 0.027]. Our observations suggest that the G allele protects against the onset of ILD and that the AA genotype is a risk factor for lung injury in PM patients.

NFKB1-94ins/del polymorphism is not associated with lung injury after cardiopulmonary bypass

Nuclear factor (NF)-kappaB (NFKB1)-94ins/del is an important polymorphism that affects promoter activity of the NFKB1 gene and is potentially associated with several inflammatory diseases. We investigated the association of this polymorphism with lung injury after cardiac surgery and cardiopulmonary bypass in a prospective cohort study of 283 patients. Genotyping was performed by high resolution melting analysis; analysis indicated no association of NFKB1 with postoperative lung injury (p = 0.064). Relative risks of the del allele and the del/del genotype were 1.34 (95% CI 1.02-1.75) and 1.74 (95% CI 1.00-3.05) respectively. Logistic regression analysis (with factors including age, peripheral vascular disease and surgical duration as risk factors of lung injury after cardiac surgery with cardiopulmonary bypass) also failed to confirm that the NFKB1 genotype is influential for lung injury (p = 0.113). We conclude that, contrary to some other evidence, the NFKB1-94ins/del polymorphism is not associated with lung injury after cardiac surgery with cardiopulmonary bypass.

The role of lymph factors in lung injury, bone marrow suppression, and endothelial cell dysfunction in a primate model of trauma-hemorrhagic shock.

Studies in rodent models of trauma-hemorrhagic shock (T/HS) have shown that factors contained in the intestinal lymph are responsible for acute lung injury and bone marrow suppression, and that they contribute to a systemic inflammatory state. Because results observed in rodent T/HS models may not fully reflect the response of injured patients, it is necessary to determine if these results can be replicated in primates before the institution of invasive studies in humans. Thus, the three goals of this study were to determine if diversion of thoracic duct lymph reduced T/HS-induced lung injury; to compare the biologic activity of thoracic duct lymph from baboons subjected to T/HS or trauma sham-shock (T/SS); and to compare the biologic activity and composition of plasma from baboons subjected to T/SS, T/HS, and T/HS with thoracic duct lymph drainage. Three groups of baboons were studied: T/SS plus lymph diversion via a thoracic duct catheter, T/HS, and T/HS plus lymph diversion (T/HS-LD). The trauma component consisted of a neck dissection with resection of the proximal clavicle plus a laparotomy. HS was to a mean arterial pressure of 40 mmHg and was maintained at 40 mmHg until the base excess reached -5 mEq or the total shock period reached 3 h. Volume resuscitation was carried out by reinfusing the shed blood plus crystalloids. Before, during, and after the T/HS or T/SS period, blood and lymph samples were obtained for analysis, and lung samples were harvested for measurement of lung wet-to-dry ratio at 5 h after the end of the shock period. Diversion of thoracic duct lymph prevented T/HS-induced lung injury as reflected in lung wet-to-dry weight ratios (T/SS = 4.6 +/- 0.5; T/HS+LD = 4.8 +/- 0.7; T/HS = 5.4 +/- 0.6; P < 0.05). Lymph from the T/HS group collected during the early postshock period was cytotoxic for human endothelial cells (HUVECs; 16% vs. 100% survival in T/SS lymph) and increased HUVEC monolayer permeability almost 2-fold (P < 0.01). T/HS lymph and plasma also suppressed red blood cell (erythroid burst-forming unit) and white blood cell (granulocyte-monocyte colony-forming unit) progenitor cell growth of human bone marrow to approximately 50% of control, whereas T/SS lymph and plasma were not suppressive (P < 0.05). Plasma cytokine levels were increased to a similar degree in the two T/HS groups. Thus, in a primate model of T/HS, gut-derived factors carried in the lymph potentiates lung injury and endothelial dysfunction, and suppresses bone marrow progenitor cell growth.

Role of tumour necrosis factor in lung injury caused by intestinal ischaemia-reperfusion.

Despite the well known inflammatory effects of tumour necrosis factor alpha (TNF), the mechanism of TNF-mediated lung injury following ischaemia-reperfusion (I/R) is still unclear. In this study, the role of TNF in the development of acute lung injury following intestinal I/R was investigated. Male Wistar rats underwent either sham operation (n = 10), 1 h of superior mesenteric artery occlusion and 2 h of reperfusion (I/R, n = 10), or pretreatment with anti-TNF polyclonal antibody 2 mg/kg and I/R (n = 6). Lung injury was evaluated by Evans blue dye concentration, immunohistochemical staining and morphometric analysis. Intestinal injury was assessed by Evans blue dye concentration and histological examination. Intestinal I/R resulted in lung injury characterized by an increase in Evans blue dye concentration, neutrophil sequestration, and obvious staining for expression of pulmonary CD11b and CD18. Pretreatment of animals with anti-TNF antibody led to a reduction in the sequestration of neutrophils, and a decrease in expression of pulmonary intracellular adhesion molecule 1 and CD18. Anti-TNF antibody pretreatment also reduced the intestinal microvascular injury but not histological grade after intestinal I/R. Treatment with an anti-TNF antibody resulted in a significant attenuation of lung injury following intestinal I/R. The data indicate that TNF is an important trigger for upregulation of pulmonary endothelial and neutrophil adhesion molecules after intestinal I/R.

Role of tumour necrosis factor in lung injury caused by intestinal ischaemia–perfusion

Abstract Background Despite the well known inflammatory effects of tumour necrosis factor (TNF), the mechanism of TNF-mediated lung injury following ischaemia–reperfusion (IR) is still unclear. In this study, the role of TNF in the development of acute lung injury following intestinal IR was investigated. Methods Male Wistar rats underwent either sham operation (n = 10) or 1 h of superior mesenteric artery occlusion and 2 h of reperfusion (IR; n = 10) or pretreatment with anti-TNF polyclonal antibody 2 mg kg−1 and IR (n = 6). Lung injury was evaluated by Evans blue dye concentration, immunohistochemical staining and morphometric analysis. Intestinal injury was assessed by Evans blue dye concentration and histological examination. Results Intestinal IR resulted in lung injury characterized by an increase in Evans blue dye concentration, polymorphonuclear neutrophil (PMN) sequestration, and obvious staining for expression of pulmonary CD11b and CD18. Pretreatment of animals with anti-TNF antibodies led to a reduction in the sequestration of PMNs (P &amp;lt; 0·05), a decrease in expression of pulmonary intercellular adhesion molecule 1 and CD18 (P &amp;lt; 0·01), and a diminished histological grade compared with the IR-only group. Anti-TNF antibody pretreatment also reduced the intestinal microvascular injury after intestinal IR. Conclusion Treatment with an anti-TNF antibody resulted in significant attenuation of lung injury following intestinal IR, which is at least partially TNF mediated. The data indicate that TNF is an important trigger for upregulation of pulmonary endothelial and neutrophil adhesion molecules after intestinal IR.

Changes of basic fibroblast growth factor in lung injury induced by combined injury

Changes of basic fibroblast growth factor in lung injury induced by combined injury

The role of complement-derived chemotactic factors in lung injury induced by preformed immune complexes.

Our previous studies have suggested a role for complement fragments presumably activated by immune complexes in patients with hypersensitivity pneumonitis. The present study has shown that circulating complement depletion by cobra venom factor resulted in the reduction in severity of immune-complex-mediated pulmonary inflammation. The activity of chemotactic factors for neutrophils generated in bronchoalveolar lavage fluids in complement-depleted animals was significantly diminished to 61.2% compared to the undepleted animals. In addition, reduced activity of chemotactic factors resulted in a marked reduction of accumulation of neutrophils in bronchoalveolar lavage fluids indicating that chemotactic factors play an important role in the sequestration of neutrophils on the alveolar side of the lung. In conclusion, chemotactic factors in bronchoalveolar lavage fluids which preceded the accumulation of polymorphonuclear cells are partially derived from complement.