Plasminogen Activator Inhibitor-1 in Cigarette Smoke Exposure and Influenza A Virus Infection-Induced Lung Injury

Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE), which contributes to chronic obstructive pulmonary disease (COPD). Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV) infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT) mice with passive CSE (PCSE), p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC apoptosis and lung inflammation. Further, inhibition of p53-mediated induction of PAI-1 by treatment of WT mice with caveolin-1 scaffolding domain peptide (CSP) reduced PCSE-induced lung inflammation and reversed PCSE-induced suppression of eosinophil-associated RNase1 (EAR1). Competitive inhibition of the p53-PAI-1 mRNA interaction by expressing p53-binding 3\u27UTR sequences of PAI-1 mRNA likewise suppressed CS-induced PAI-1 and AEC apoptosis and restored EAR1 expression. Consistent with PCSE-induced lung injury, IAV infection increased p53, PAI-1 and apoptosis in AECs in association with pulmonary inflammation. Lung inflammation induced by PCSE was worsened by subsequent exposure to IAV. Mice lacking PAI-1 that were exposed to IAV showed minimal viral burden based on M2 antigen and hemagglutination analyses, whereas transgenic mice that overexpress PAI-1 without PCSE showed increased M2 antigen and inflammation after IAV infection. These observations indicate that increased PAI-1 expression promotes AEC apoptosis and exacerbates lung inflammation induced by IAV following PCSE

The CTSA University of Texas Health Science Center (UTHSC) Northeast—Tyler and Rio Grande Valley Success Story: How Rural, Underserved Academic Communities Rapidly Built a Robust Engine for Collaborative COVID-19 Clinical Research

In 2018, The University of Texas Health Science Center– Tyler and University of Texas Rio Grande Valley were invited to develop clinical research units for an existing Clinical and Translational Science Award (CTSA) consortium with the objective to equip medically underserved, economically disadvantaged communities and subsequently to deploy COVID-19 clinical trials in response to a public health emergency

Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema

The incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A Streptococcus pneumoniae-induced rabbit model of chronic empyema recapitulates the progression, loculation, fibrotic repair, and pleural thickening of human disease. Treatment with single chain (sc) urokinase (scuPA) or tissue type (sctPA) plasminogen activators in doses 1.0–4.0 mg/kg were only partially effective in this model. Docking Site Peptide (DSP; 8.0 mg/kg), which decreased the dose of sctPA for successful fibrinolytic therapy in acute empyema model did not improve efficacy in combination with 2.0 mg/kg scuPA or sctPA. However, a two-fold increase in either sctPA or DSP (4.0 and 8.0 mg/kg or 2.0 and 16.0 mg/kg sctPA and DSP, respectively) resulted in 100% effective outcome. Thus, DSP-based Plasminogen Activator Inhibitor 1-Targeted Fibrinolytic Therapy (PAI-1-TFT) of chronic infectious pleural injury in rabbits increases the efficacy of alteplase rendering ineffective doses of sctPA effective. PAI-1-TFT represents a novel, well-tolerated treatment of empyema that is amenable to clinical introduction. The chronic empyema model recapitulates increased resistance of advanced human empyema to fibrinolytic therapy, thus allowing for studies of muti-injection treatments

Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection: Innate Immunity

Tissue Factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TFΔ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2 like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth

Caveolin-1-Related Intervention for Fibrotic Lung Diseases

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD) for which there are no effective treatments. Lung transplantation is the only viable option for patients with end-stage PF but is only available to a minority of patients. Lung lesions in ILDs, including IPF, are characterized by alveolar epithelial cell (AEC) senescence and apoptosis and accumulation of activated myofibroblasts and/or fibrotic lung (fL) fibroblasts (fLfs). These composite populations of fLfs show a high rate of basal proliferation, resist apoptosis and senescence, and have increased migration and invasiveness. They also more readily deposit ECM proteins. These features eventuate in progressive destruction of alveolar architecture and loss of lung function in patients with PF. The identification of new, safer, and more effective therapy is therefore mandatory for patients with IPF or related ILDs. We found that increased caveolin-1 and tumor suppressor protein, p53 expression, and apoptosis in AECs occur prior to and then with the proliferation of fLfs in fibrotic lungs. AECs with elevated p53 typically undergo apoptosis. fLfs alternatively demonstrate strikingly low basal levels of caveolin-1 and p53, while mouse double minute 2 homolog (mdm2) levels and mdm2-mediated degradation of p53 protein are markedly increased. The disparities in the expression of p53 in injured AECs and fLfs appear to be due to increased basal expression of caveolin-1 in apoptotic AECs with a relative paucity of caveolin-1 and increased mdm2 in fLfs. Therefore, targeting caveolin-1 using a caveolin 1 scaffolding domain peptide, CSP7, represents a new and promising approach for patients with IPF, perhaps other forms of progressive ILD or even other forms of organ injury characterized by fibrotic repair. The mechanisms of action differ in the injured AECs and in fLfs, in which differential signaling enables the preservation of AEC viability with concurrent limitation of fLf expansion and collagen secretion. The findings in three models of PF indicate that lung scarring can be nearly abrogated by airway delivery of the peptide. Phase 1 clinical trial testing of this approach in healthy volunteers has been successfully completed; Phase 1b in IPF patients is soon to be initiated and, if successful, will be followed by phase 2 testing in short order. Apart from the treatment of IPF, this intervention may be applicable to other forms of tissue injury characterized by fibrotic repair

Caveolin-1-Related Intervention for Fibrotic Lung Diseases

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD) for which there are no effective treatments. Lung transplantation is the only viable option for patients with end-stage PF but is only available to a minority of patients. Lung lesions in ILDs, including IPF, are characterized by alveolar epithelial cell (AEC) senescence and apoptosis and accumulation of activated myofibroblasts and/or fibrotic lung (fL) fibroblasts (fLfs). These composite populations of fLfs show a high rate of basal proliferation, resist apoptosis and senescence, and have increased migration and invasiveness. They also more readily deposit ECM proteins. These features eventuate in progressive destruction of alveolar architecture and loss of lung function in patients with PF. The identification of new, safer, and more effective therapy is therefore mandatory for patients with IPF or related ILDs. We found that increased caveolin-1 and tumor suppressor protein, p53 expression, and apoptosis in AECs occur prior to and then with the proliferation of fLfs in fibrotic lungs. AECs with elevated p53 typically undergo apoptosis. fLfs alternatively demonstrate strikingly low basal levels of caveolin-1 and p53, while mouse double minute 2 homolog (mdm2) levels and mdm2-mediated degradation of p53 protein are markedly increased. The disparities in the expression of p53 in injured AECs and fLfs appear to be due to increased basal expression of caveolin-1 in apoptotic AECs with a relative paucity of caveolin-1 and increased mdm2 in fLfs. Therefore, targeting caveolin-1 using a caveolin 1 scaffolding domain peptide, CSP7, represents a new and promising approach for patients with IPF, perhaps other forms of progressive ILD or even other forms of organ injury characterized by fibrotic repair. The mechanisms of action differ in the injured AECs and in fLfs, in which differential signaling enables the preservation of AEC viability with concurrent limitation of fLf expansion and collagen secretion. The findings in three models of PF indicate that lung scarring can be nearly abrogated by airway delivery of the peptide. Phase 1 clinical trial testing of this approach in healthy volunteers has been successfully completed; Phase 1b in IPF patients is soon to be initiated and, if successful, will be followed by phase 2 testing in short order. Apart from the treatment of IPF, this intervention may be applicable to other forms of tissue injury characterized by fibrotic repair