transforming-growth-factor-beta and Respiratory-Tract-Infections

The lung is under constant pressure to protect the body from invading bacteria. An effective inflammatory immune response must be tightly orchestrated to ensure complete clearance of any invading bacteria, while simultaneously ensuring that inflammation is kept under strict control to preserve lung viability. Chronic bacterial lung infections are seen as a major threat to human life with the treatment of these infections becoming more arduous as the prevalence of antibiotic resistance becomes increasingly commonplace. In order to survive within the lung bacteria target the host immune system to prevent eradication. Many bacteria directly target inflammatory cells and cytokines to impair inflammatory responses. However, bacteria also have the capacity to take advantage of and strongly promote anti-inflammatory immune responses in the host lung to inhibit local pro-inflammatory responses that are critical to bacterial elimination. Host cells such as T regulatory cells and myeloid-derived suppressor cells are often enhanced in number and activity during chronic pulmonary infection. By increasing suppressive cell populations and cytokines, bacteria promote a permissive environment suitable for their prolonged survival. This review will explore the anti-inflammatory aspects of the lung immune system that are targeted by bacteria and how bacterial-induced immunosuppression could be inhibited through the use of host-directed therapies to improve treatment options for chronic lung infections.

Topics: Animals; Antibodies, Monoclonal; Bacterial Infections; BCG Vaccine; Dendritic Cells; Humans; Immune Tolerance; Interleukin-10; Lung; Macrophages, Alveolar; Myeloid-Derived Suppressor Cells; Respiratory Tract Infections; Transforming Growth Factor beta

Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven neoplastic disorder of the upper aerodigestive tract that causes significant morbidity and can lead to fatal airway obstruction. Prior clinical study demonstrated clinical benefit with the programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Bintrafusp alpha is a bifunctional inhibitor of PD-L1 and transforming growth factor-beta (TGF-b) that has shown clinical activity in several cancer types.. We conducted a phase II clinical trial evaluating bintrafusp alpha in adults with RRP. Papilloma samples before and after treatment with bintrafusp alpha were assessed for correlates of response with multiplex immunofluorescence as well as immunological and genomic analyses. Post hoc analyses of papilloma samples before and after treatment with avelumab were assessed for comparison.. Dual PD-L1/TGF-b inhibition failed to abrogate papilloma growth in most subjects and increased the frequency of clinically indicated interventions after treatment in four of eight subjects based on each subject's own historical control. TGF-b neutralization consistently decreased pSMAD3 and p21 and increased Ki67 expression within the basal layers of papillomas, indicating that TGF-b restrained proliferation. These alterations were not observed in papillomas treated with PD-L1 blockade alone. Dual PD-L1/TGF-b inhibition did not enhance anti-HPV immunity within papillomas beyond that observed with PD-L1 blockade. Genomic alterations in TGF-b superfamily genes were infrequent in papillomas and normal mucosa but present in a significant fraction of head and neck carcinomas.. Intact TGF-b signaling restrains proliferation within papillomas, and the use of clinical agents that abrogate this pathway should be avoided in patients with RRP.. NCT03707587 and NCT02859454.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Female; Humans; Immune Checkpoint Inhibitors; Immunologic Factors; Immunotherapy; Mice; NIH 3T3 Cells; Papilloma; Papillomavirus Infections; Respiratory Tract Infections; Transforming Growth Factor beta; Tumor Microenvironment

The role of natural killer (NK) cells in juvenile-onset recurrent respiratory papillomatosis (JORRP) patients remains elusive. In this study, we find increased NK cell percentage, particularly CD11b-CD27- (DN) subsets in peripheral blood of JORRP patients and associated with disease activity. RNA sequencing shows a downregulated "natural killer cell-mediated cytotoxicity" feature in JORRP tumors. We also find impaired cytotoxic capacity and lower expression of NK cell-activating receptors including NKp30 and NKp46. Higher transforming growth factor-beta 1 (TGF-β1) is found both in plasma and tumor tissues of JORRP, and anti-TGF-β1 antibody could restore NK cell cytolytic activity and upregulate NKp30 and NKG2D expression. Also, we find a significantly higher Chemokine receptor type 6 (CXCR6) on NK cells in tumors compared with that in peripheral blood. Finally, RT-PCR analysis show that both HPV6-E6-E7 and HPV11-E6-E7 overexpression leads to higher

Topics: Humans; Killer Cells, Natural; Papilloma; Papillomavirus Infections; Receptors, Natural Killer Cell; Respiratory Tract Infections; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Disease Progression; Human papillomavirus 11; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-4; Killer Cells, Natural; Natural Cytotoxicity Triggering Receptor 3; Neoplasm Recurrence, Local; Papilloma; Papillomavirus Infections; Respiratory Tract Infections; Transforming Growth Factor beta

Colonization of the upper respiratory tract is an initial step that may lead to disease for many pathogens. To prevent compromise of the epithelial barrier, the host must monitor and tightly control bacterial levels on the mucosa. Here we show that innate immune functions of respiratory epithelial cells control colonization by Streptococcus pneumoniae and Haemophilus influenzae in a Toll-like receptor (TLR)-dependent manner. Activation of inflammatory pathways, including mitogen-activated protein kinase signaling, in respiratory epithelial cells was accompanied by the induction of the transforming growth factor beta signaling cascade during early colonization. Thus, colonization resulted in upregulation of factors involved in a proinflammatory response (e.g., interleukin-6) as well as factors known to modulate the epithelial barrier (e.g., Snail-1). These in vivo data provided a link between inflammation control and maintenance of the mucosal barrier function during infection and emphasized the importance of TLR-dependent inflammatory responses of the respiratory epithelium.

Topics: Animals; Cytokines; Epithelium; Female; Haemophilus influenzae; Mice; Mice, Inbred C57BL; Nasopharynx; Respiratory Tract Infections; Signal Transduction; Streptococcus pneumoniae; Toll-Like Receptors; Transforming Growth Factor beta

Chronic inflammation and fibrosis are hallmarks of lung pathology of newborn Ureaplasma infection. We hypothesized that antenatally acquired Ureaplasma stimulates a chronic inflammatory, profibrotic immune response that contributes to lung injury, altered developmental signaling, and fibrosis. Lung specimens from 125-d gestation baboon newborns ventilated for 14 d that were either infected antenatally with Ureaplasma serovar 1 or noninfected, and 125-d and 140-d gestational controls were obtained from the Baboon BPD Resource Center (San Antonio, TX). Trichrome stain to assess fibrosis and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA) and transforming growth factor beta1 (TGFbeta1) were performed. Lung homogenates were analyzed by enzyme-linked immunosorbent assay (ELISA) for cytokines [tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta, TGFbeta1, oncostatin M (OSM), IL-10, and interferon gamma (IFNgamma)] and the chemokine MCP-1 and by Western blot for Smad2, Smad3, and Smad7. Compared with noninfected ventilated and gestational controls, Ureaplasma-infected lungs demonstrated more extensive fibrosis, increased alpha-SMA and TGFbeta1 immunostaining, and higher concentrations of active TGFbeta1, IL-1beta, and OSM, but no difference in IL-10 levels. There was a trend toward higher Smad2/Smad7 and Smad3/Smad7 ratios in Ureaplasma lung homogenates, consistent with up-regulation of TGFbeta1 signaling. Collectively, these data suggest that a prolonged proinflammatory response initiated by intrauterine Ureaplasma infection contributes to early fibrosis and altered developmental signaling in the immature lung.

Topics: Actins; Animals; Animals, Newborn; Chemokine CCL2; Cytokines; In Vitro Techniques; Inflammation Mediators; Lung; Muscle, Smooth; Papio; Premature Birth; Pulmonary Fibrosis; Respiration, Artificial; Respiratory Tract Infections; Smad Proteins; Transforming Growth Factor beta; Ureaplasma Infections; Ureaplasma urealyticum

Because chronic Mycoplasma pneumoniae respiratory infection is hypothesized to play a role in asthma, the potential of M. pneumoniae to establish chronic respiratory infection with associated pulmonary disease was investigated in a murine model. BALB/c mice were intranasally inoculated once with M. pneumoniae and examined at 109, 150, 245, 368, and 530 days postinoculation. M. pneumoniae was detected in bronchoalveolar lavage fluid by culture or PCR in 70 and 22% of mice at 109 and 530 days postinoculation, respectively. Lung histopathology was normal up to 368 days postinoculation. At 530 days, however, 78% of the mice inoculated with M. pneumoniae demonstrated abnormal histopathology characterized by peribronchial and perivascular mononuclear infiltrates. A mean histopathologic score (HPS) at 530 days of 5.1 was significantly greater (P < 0.01) than that for controls (HPS score of 0). Serum anti-M. pneumoniae immunoglobulin G was detectable in all of the mice inoculated with M. pneumoniae and was inversely correlated with HPS (r = -0.95, P = 0.01) at 530 days postinoculation. Unrestrained whole-body plethysmography measurement of enhanced pause revealed significantly elevated airway methacholine reactivity in M. pneumoniae-inoculated mice compared with that in controls at 245 days (P = 0.03) and increased airway obstruction at 530 days (P = 0.01). Murine M. pneumoniae respiratory infection can lead to chronic pulmonary disease characterized by airway hyperreactivity, airway obstruction, and histologic inflammation.

Topics: Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Chronic Disease; Female; Interleukin-4; Interleukin-6; Mice; Mice, Inbred BALB C; Mycoplasma pneumoniae; Plethysmography; Pneumonia, Mycoplasma; Respiratory Tract Infections; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Parainfluenza type 1 (Sendai) virus infection in young rats induces airway growth abnormalities associated with persistent pulmonary dysfunction and hyperresponsiveness. The objectives of this study were to compare virus-susceptible brown Norway (BN) rats and virus-resistant F344 rats and to determine which of several virus-induced structural abnormalities, including bronchiolar hypoplasia, alveolar dysplasia, bronchiolar mural fibrosis, and increases in bronchiolar mast cells, were associated with virus-induced increases in pulmonary resistance and hyperresponsiveness to methacholine. We also determined whether bronchiolar mural thickening and fibrosis may be caused by increased bronchiolar expression of cytokines such as TGF-beta 1 into airways. BN rats infected with virus developed increases in respiratory resistance and hyperresponsiveness that persisted for 28 to 65 d after inoculation. Functional abnormalities were most strongly associated with bronchiolar mural thickening and fibrosis as well as with recruitment of inflammatory cells, including macrophages, mast cells, lymphocytes, and eosinophils, into the bronchiolar wall. F344 rats were resistant to significant virus-induced alterations in bronchiolar airway wall thickness and mast cell increases as well as to pulmonary function abnormalities. BN rats had increase pulmonary mRNA levels of TGF-beta 1 at 10 and 14 d after viral inoculation as compared with F344 rats. BN rats also had greater numbers of bronchiolar macrophages expressing TGF-beta 1 protein that were localized in bronchiolar walls at 10, 14, and 30 d after inoculation. We conclude that recruitment and persistence of airway inflammatory cells and airway wall fibrosis may be important alterations induced by viral lower respiratory disease during early life that can lead to long-term airway dysfunction and hyperresponsiveness. Virus-induced airway fibrosis may be mediated in part by increased TGF-beta 1 gene expression by bronchiolar macrophages in genetically susceptible individuals.

Topics: Airway Resistance; Animals; Animals, Newborn; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Disease Susceptibility; Fibrosis; Immunohistochemistry; In Situ Hybridization; Inflammation; Lung; Lung Compliance; Macrophages; Mast Cells; Methacholine Chloride; Parainfluenza Virus 1, Human; Rats; Rats, Inbred BN; Rats, Inbred F344; Respiratory Mechanics; Respiratory Tract Infections; Respirovirus Infections; Transforming Growth Factor beta

Topics: Animals; Asthma; Bronchial Provocation Tests; Cells, Cultured; Histamine; In Vitro Techniques; Inflammation; Interleukin-1; Interleukin-11; Interleukin-4; Lung; Mice; Mice, Inbred BALB C; Respiratory Tract Infections; Transforming Growth Factor beta; Virus Diseases