Keratinocyte growth factor supports pulmonary innate immune defense through maintenance of alveolar antimicrobial protein levels and macrophage function

Keratinocyte growth factor (KGF) is an epithelial mitogen that has been reported to protect the lungs from a variety of toxic and infectious insults. In prior studies we found that recombinant human KGF accelerates clearance of bacteria from the murine lung by augmenting the function of alveolar macrophages (AM). In this study we tested the hypothesis that endogenous KGF plays a role in the maintenance of innate pulmonary defense against gram-negative bacterial infections. KGF-deficient mice exhibited delayed clearance of Escherichia coli from the lungs, attenuated phagocytosis by AM, and decreased antimicrobial activity in bronchoalveolar lavage (BAL) fluid, due in part to reductions in levels of surfactant protein A, surfactant protein D, and lysozyme. These immune deficits were accompanied by lower alveolar type II epithelial cell counts and reduced alveolar type II epithelial cell expression of collectin and lysozyme genes on a per cell basis. No significant between-group differences were detected in selected inflammatory cytokines or BAL inflammatory cell populations at baseline or after bacterial challenge in the wild-type and KGF-deficient mice. A single intranasal dose of recombinant human KGF reversed defects in bacterial clearance, AM function, and BAL fluid antimicrobial activity. We conclude that KGF supports alveolar innate immune defense through maintenance of alveolar antimicrobial protein levels and functions of AM. Together these data demonstrate a role for endogenous KGF in maintenance of normal pulmonary innate immune function.

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Design-based stereological analysis of the lung parenchymal architecture and alveolar type II cells in surfactant protein A and D double deficient mice

The Anatomical Record Part A Discoveries in Molecular Cellular and Evolutionary Biology ◽

10.1002/ar.a.20225 ◽

2005 ◽

Vol 286A (2) ◽

pp. 885-890 ◽

Cited By ~ 25

Author(s):

Anja Jung ◽

Lennell Allen ◽

Jens R. Nyengaard ◽

Hans Jørgen G. Gundersen ◽

Joachim Richter ◽

...

Keyword(s):

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Alveolar Type ◽

Type Ii Cells ◽

Type Ii ◽

Alveolar Type Ii Cells ◽

Stereological Analysis ◽

Deficient Mice

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2P-0395 Surfactant protein D of the innate immune defense is negatively associated with obesity

Atherosclerosis Supplements ◽

10.1016/s1567-5688(03)90537-x ◽

2003 ◽

Vol 4 (2) ◽

pp. 125

Author(s):

U. Holmskov ◽

G. Lyster ◽

J. Hjelmborg ◽

R. Leth-Larsen ◽

V. Moeller ◽

...

Keyword(s):

Surfactant Protein ◽

Immune Defense ◽

Innate Immune ◽

Surfactant Protein D ◽

Negatively Associated ◽

Innate Immune Defense

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Alveolar Type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2014.03.008 ◽

2014 ◽

Vol 33 (7) ◽

pp. 758-765 ◽

Cited By ~ 21

Author(s):

Raquel Guillamat-Prats ◽

Gemma Gay-Jordi ◽

Antoni Xaubet ◽

Victor I. Peinado ◽

Anna Serrano-Mollar

Keyword(s):

Cell Transplantation ◽

Lung Fibrosis ◽

Pulmonary Surfactant ◽

Surfactant Protein ◽

Alveolar Type ◽

Type Ii ◽

Protein Levels ◽

Alveolar Type Ii Cell ◽

Type Ii Cell ◽

Pulmonary Surfactant Protein

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Respiratory syncytial virus infection alters surfactant protein A expression in human pulmonary epithelial cells by reducing translation efficiency

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90507.2008 ◽

2009 ◽

Vol 297 (4) ◽

pp. L559-L567 ◽

Cited By ~ 16

Author(s):

Shirley R. Bruce ◽

Constance L. Atkins ◽

Giuseppe N. Colasurdo ◽

Joseph L. Alcorn

Keyword(s):

Steady State ◽

Protein A ◽

Surfactant Protein ◽

Innate Immune ◽

Surfactant Protein A ◽

Translation Efficiency ◽

Type Ii ◽

Protein Levels ◽

Rsv Infection ◽

Syncytial Virus

Infection of neonatal lung by respiratory syncytial virus (RSV) is a common cause of respiratory dysfunction. Lung alveolar type II and bronchiolar epithelial (Clara) cells secrete surfactant protein A (SP-A), a collectin that is an important component of the pulmonary innate immune system. SP-A binds to the virus, targeting the infectious agent for clearance by host defense mechanisms. We have previously shown that while the steady-state level of SP-A mRNA increases approximately threefold after RSV infection, steady-state levels of cellular and secreted SP-A protein decrease 40–60% in human type II cells in primary culture, suggesting a mechanism where the virus alters components of the innate immune response in infected cells. In these studies, we find that changes in SP-A mRNA and protein levels in RSV-infected NCI-H441 cells (a bronchiolar epithelial cell line) recapitulate the results in SP-A expression observed in primary lung cells. While SP-A protein is normally ubiquitinated, there is no change in the level of SP-A protein ubiquitination or proteasome activity during RSV infection, suggesting that the reduced levels of SP-A protein are not due to degradation by activated proteasomes. SP-A mRNA is appropriately processed and exported from the nucleus to the cytoplasm during RSV infection. As evidenced by polysome analysis of SP-A mRNA and pulse-chase analysis of newly synthesized SP-A protein, we find a decrease in translational efficiency that is specific for SP-A mRNA. Therefore, the decrease in SP-A protein levels observed after RSV infection of pulmonary bronchiolar epithelial cells results from a mechanism that affects SP-A mRNA translation efficiency.

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RNase 7, a Novel Innate Immune Defense Antimicrobial Protein of Healthy Human Skin

Journal of Biological Chemistry ◽

10.1074/jbc.m207587200 ◽

2002 ◽

Vol 277 (48) ◽

pp. 46779-46784 ◽

Cited By ~ 281

Author(s):

Jürgen Harder ◽

Jens-Michael Schröder

Keyword(s):

Human Skin ◽

Immune Defense ◽

Innate Immune ◽

Antimicrobial Protein ◽

Healthy Human ◽

Innate Immune Defense

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LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2106685118 ◽

2021 ◽

Vol 118 (35) ◽

pp. e2106685118

Author(s):

Yujie Tian ◽

Jiaoyan Lv ◽

Ziyan Su ◽

Tao Wu ◽

Xiaoguang Li ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Immune Responses ◽

Respiratory Diseases ◽

Innate Immune ◽

Alveolar Type ◽

Type Ii ◽

Innate Immune Responses ◽

Leucine Rich Repeat ◽

Cell Dysfunction ◽

Deficient Mice

Perturbation of lung homeostasis is frequently associated with progressive and fatal respiratory diseases, such as pulmonary fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in healthy lungs, but its functions in lung homeostasis and diseases remain elusive. Herein, we showed that LRRK2 expression was clearly reduced in mammalian fibrotic lungs, and LRRK2-deficient mice exhibited aggravated bleomycin-induced pulmonary fibrosis. Furthermore, we demonstrated that in bleomycin-treated mice, LRRK2 expression was dramatically decreased in alveolar type II epithelial (AT2) cells, and its deficiency resulted in profound dysfunction of AT2 cells, characterized by impaired autophagy and accelerated cellular senescence. Additionally, LRRK2-deficient AT2 cells showed a higher capacity of recruiting profibrotic macrophages via the CCL2/CCR2 signaling, leading to extensive macrophage-associated profibrotic responses and progressive pulmonary fibrosis. Taken together, our study demonstrates that LRRK2 plays a crucial role in preventing AT2 cell dysfunction and orchestrating the innate immune responses to protect against pulmonary fibrosis.

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The roles of grouper TANK in innate immune defense against iridovirus and nodavirus infections

Fish & Shellfish Immunology ◽

10.1016/j.fsi.2020.06.017 ◽

2020 ◽

Vol 104 ◽

pp. 506-516

Author(s):

Jingguang Wei ◽

Chen Li ◽

Jisheng Ou ◽

Xin Zhang ◽

Zetian Liu ◽

...

Keyword(s):

Immune Defense ◽

Innate Immune ◽

Innate Immune Defense

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Surfactant metabolic consequences of overexpression of GM-CSF in the epithelium of GM-CSF-deficient mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.273.4.l709 ◽

1997 ◽

Vol 273 (4) ◽

pp. L709-L714 ◽

Cited By ~ 13

Author(s):

Machiko Ikegami ◽

Alan H. Jobe ◽

Jacquelyn A. Huffman Reed ◽

Jeffrey A. Whitsett

Keyword(s):

Lung Tissue ◽

Surfactant Protein ◽

Type Ii ◽

Cell Numbers ◽

Gm Csf ◽

Type Ii Cell ◽

Macrophage Colony ◽

Respiratory Epithelial ◽

Deficient Mice ◽

Surfactant Metabolism

Granulocyte macrophage colony-stimulating factor (GM-CSF) is a regulator of surfactant metabolism because GM-CSF-deficient mice have abnormally slow clearance and catabolism of saturated phosphatidylcholine (Sat PC) and surfactant protein (SP)-A in airspaces and lung tissue. Overexpression of GM-CSF only in respiratory epithelial cells of mice deficient in GM-CSF using the SP-C promotor (GM−/−,SP-C-GM+/+) resulted in increased type II cell numbers and normalization of alveolar Sat PC pool sizes. Metabolic measurements demonstrated that incorporation of radiolabeled choline and palmitate was increased more than twofold, but the amount of radiolabeled Sat PC that accumulated in airspaces relative to the amount incorporated was decreased by 50% relative to normal GM+/+ mice. The clearance of dipalmitoylphosphatidylcholine and SP-B from the airspaces was more rapid for GM−/−,SP-C-GM+/+ mice than for GM+/+ mice. Loss of Sat PC and SP-B from the lungs (alveolar plus lung tissue) was similar in the two strains of mice. The normal surfactant pools in the GM−/−,SP-C-GM+/+ mice were achieved by the net effects of increases in type II cell numbers, increased incorporation, decreased accumulation, and increased reuptake rates for surfactant components, demonstrating the multiple effects of GM-CSF on surfactant metabolism.

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