Fibrocytes and the pathogenesis of diffuse parenchymal lung disease

Fibrosis is fundamental to the pathogenesis of many chronic lung diseases, including some lung infections, airway diseases such as bronchiectasis and asthma, and most of the diffuse parenchymal lung diseases. Idiopathic pulmonary fibrosis, the prototypical fibrotic lung disease, is amongst the most common diffuse parenchymal lung diseases and is characterized by progressive decline in lung function and premature death from respiratory failure. The clinical management of patients with this illness is hampered by our current inability to predict clinical deterioration and lack of an effective therapy. Fibrocytes are a population of bone marrow-derived circulating progenitor cells that home to injured tissues and differentiate into fibroblasts and myofibroblasts, thus contributing to scar formation. We summarize the evidence supporting the role of these cells in the pathogenesis of fibrotic lung diseases

The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease

The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance between the pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors pro-inflammatory mediators dictating the development of chronic diffuse lung disease. This review focuses on the mediators that influence this imbalance

The role of fibrocytes in fibrotic diseases of the lungs and heart

Fibrosis is the end result of a complex series of events that follow tissue injury and inflammation. Pathophysiologic fibrosis results in permanent scar formation, and can impair organ function. Fibrocytes are circulating, bone-marrow-derived progenitor cells that traffic from the bone marrow to the injured organ via the bloodstream, where they differentiate into fibroblasts and myofibroblasts, and play a pivotal role in both physiologic and aberrant fibrosis. In this review, we focus on the contribution of fibrocytes to fibrotic diseases of the lungs and the heart, including interstitial lung diseases, asthma, pulmonary hypertension, atherosclerosis and ischemic cardiomyopathy

The Role of Interleukin-8 in the Infectious Process a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73887/1/j.1749-6632.1994.tb44245.x.pd

Endogenously produced urokinase amplifies tumor necrosis factor‐α secretion by THP‐1 mononuclear phagocytes

This study examined the effects of endogenous urokinase (uPA) on lipopolysaccharide (LPS)‐stimulated tumor necrosis factor α (TNF‐α) secretion in THP‐1 mononuclear phagocytes. Anti‐uPA monoclonal antibody (mAb) suppressed LPS‐driven TNF‐α secretion by 61.6 ± 5.9% (P < .001), and PAI‐1, a uPA inhibitor, suppressed it to 53.1 ± 8.2% of the control value (P < .001). Up‐regulation of TNF‐α mRNA was suppressed in parallel with secreted TNF‐α protein. TNF‐α secretion was unaffected by depleting plasminogen or by aprotinin, a plasmin inhibitor. When endogenous uPA was displaced from the cell, exogenous high‐molecular‐weight (intact) uPA augmented LPS‐driven TNF‐α secretion. By contrast, a uPA fragment containing the catalytic domain was inhibitory, and the uPA receptor‐binding domain had no effect. We conclude that endogenous uPA amplifies TNF‐α neosynthesis of UPS‐stimulated THP‐1 mononuclear phagocytes. The effect requires intact uPA and is independent of plasmin activity. This represents a novel mechanism by which a mononuclear phagocyte–derived protease contributes to generating proinflammatory signals.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142208/1/jlb0302.pd

TNF and IL‐6 mediate MIP‐1α expression in bleomycin‐induced lung injury

Previously, macrophage inflammatory protein‐1α (MIP‐1α), a member of the C‐C chemokine family, has been implicated in bleomycin‐induced pulmonary fibrosis, a model of the human disease idiopathic pulmonary fibrosis. Neutralization of MIP‐1α protein with anti‐MIP‐1α antibodies significantly attenuated both mononuclear phagocyte recruitment and pulmonary fibrosis in bleomycin‐challenged CBA/J mice. However, the specific stimuli for MIP‐1α expression in the bleomycin‐induced lesion have not been characterized. In this report, two mediators of the inflammatory response to bleomycin, tumor necrosis factor (TNF) and interleukin‐6 (IL‐6), were evaluated as putative stimuli for MIP‐1α expression after bleomycin challenge in CBA/J mice. Elevated levels of bioactive TNF and IL‐6 were detected in bronchoalveolar lavage (BAL) fluid and lung homogenates from bleomycin‐treated CBA/J mice at time points post‐bleomycin challenge, which precede MIP‐1α protein expression. Treatment of bleomycin‐challenged mice with soluble TNF receptor (sTNFr) or anti‐IL‐6 antibodies significantly decreased MIP‐1α protein expression in the lungs. Furthermore, normal alveolar macrophages secreted elevated levels of MIP‐1α protein in response to treatment with TNF plus IL‐6 or bleomycin plus IL‐6, but not TNF, bleomycin, or IL‐6 alone. Finally, leukocytes recovered from the BAL fluid of bleomycin‐challenged mice secreted higher levels of MIP‐1α protein, compared to controls, when treated with TNF alone. Based on the data presented here, we propose that TNF and IL‐6 are part of a cytokine network that modulates MIP‐1α protein expression in the profibrotic inflammatory lesion during the response to intratracheal bleomycin challenge. J. Leukoc. Biol. 64: 528–536; 1998.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141711/1/jlb0528.pd

Mononuclear Cell Adherence Induces Neutrophil Chemotactic Factor/Interleukin‐8 Gene Expression

The accumulation of polymorphonuclear cells (PMN) in tissue is an essential element of the inflammatory response that is important in host defense. Adherence to endothelium constitutes the first step in PMN migration from the vascular compartment to the interstitium. We demonstrate that human peripheral blood mononuclear cells (PBMC) adherent to plastic can result in expression of interleukin‐8 (IL‐8), a potent PMN chemoattractant and activating cytokine. Northern blot analyses showed PBMC adherent to plastic expressed IL‐8 steady‐state mRNA levels by 30 min, peaked at 8 h, and then decreased over the next 16 h. In contrast, nonadherent PBMC (cultured in teflon chambers) expressed less than 25% of the maximal IL‐8 steady‐state mRNA levels as compared with adherent PBMC. Adherent PBMC‐associated IL‐8 determined by immunohistochemistry, supernatant chemotactic bioactivity, and extracellular antigenic IL‐8 paralleled IL‐8 mRNA expression. Antigenic and bioactive IL‐8 were significantly apparent by 4–8 h, respectively, and increased significantly to maximal levels by 24 h. Furthermore, adherent PBMC IL‐8 gene expression was suppressed by either concomitant treatment with actinomycin‐D or cycloheximide, yet specific neutralizing antibodies directed against either IL‐1β or tumor necrosis factor (TNF)‐α failed to alter adherence‐induced steady‐state IL‐8 mRNA levels. These data support the hypothesis that PBMC adherence is an important signal for the production of IL‐8, and may be essential to the development of the inflammatory response through the elicrtation of PMN.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141636/1/jlb0287.pd

SLC/CCL21-mediated anti-tumor responses require IFNγ, MIG/CXCL9 and IP-10/CXCL10

BACKGROUND: SLC/CCL21, normally expressed in high endothelial venules and in T cell zones of spleen and lymph nodes, strongly attracts T cells and dendritic cells (DC). We have previously shown that SLC/CCL21-mediated anti-tumor responses are accompanied by significant induction of IFNγ and the CXC chemokines, monokine induced by IFNγ (MIG/CXCL9) and IFNγ-inducible protein-10 (IP-10/CXCL10). RESULTS: We assessed the importance of IFNγ, IP-10/CXCL10 and MIG/CXCL9 in SLC/CCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9 or IFNγ significantly reduced the anti-tumor efficacy of SLC/CCL21. Assessment of cytokine production at the tumor site showed an interdependence of IFNγ, MIG/CXCL9 and IP-10/CXCL10; neutralization of any one of these cytokines caused a concomitant decrease in all three cytokines. Similarly, neutralization of any one of these cytokines led to a decrease in the frequency of CXCR3(+ve )T cells and CD11c(+ve )DC at the tumor site. CONCLUSION: These findings indicate that the full potency of SLC/CCL21-mediated anti-tumor responses require in part the induction of IFNγ, MIG/CXCL9 and IP-10/CXCL10

Myeloid suppressor cell depletion augments antitumor activity in lung cancer.

BackgroundMyeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer.Principal findingsIndividual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFNγ, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1&amp;2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls.SignificanceOur data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion

Macrophage/fibroblast coculture induces macrophage inflammatory protein‐1a production mediated by intercellular adhesion molecule‐1 and oxygen radicals

This study examined the cell‐to‐cell interaction between fibroblasts and macrophages as a possible contributor to the chronic inflammatory state. In a coculture system, consisting of macrophages layered over confluent fibroblasts, there was a significant increase in macrophage inflammatory protein 1α (MIP‐1α) compared with control cultures. ICAM‐1 adhesion was identified as an important stimulus of MIP‐1α production by using ICAM‐1‐specific monoclonal antibodies. Furthermore, fibroblasts from ICAM‐1 knockout mice induced significantly less MIP‐1α production from peritoneal macrophages when compared to control fibroblasts. In addition, it appeared that oxygen radicals functioned as activating molecules during cellular interaction and production of MIP‐1α, as the addition of the antioxidant N‐acetylcysteine (NAC) prevented MIP‐1α secretion. Thus, the ICAM‐1 and oxygen radical‐mediated induction of MIP‐1α associated with a macrophage/fibroblast coculture system provides one possible mechanism by which immune/inflammatory cell interactions may augment chemokine production and exacerbate chronic inflammatory diseases. J. Leukoc. Biol. 64: 636–641; 1998.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141120/1/jlb0636.pd