American Journal of Respiratory Cell and Molecular Biology

Desquamative interstitial pneumonia (DIP) is a rare, smoking-related, diffuse parenchymal lung disease characterized by marked accumulation of alveolar macrophages (AMs) and emphysema, without extensive fibrosis or neutrophilic inflammation. Because smoking increases expression of pulmonary GM-CSF (granulocyte/macrophage–colony stimulating factor) and GM-CSF stimulates proliferation and activation of AMs, we hypothesized that chronic exposure of mice to increased pulmonary GM-CSF may recapitulate DIP. Wild-type (WT) mice were subjected to inhaled cigarette smoke exposure for 16 months, and AM numbers and pulmonary GM-CSF mRNA levels were measured. After demonstrating that smoke inhalation increased pulmonary GM-CSF in WT mice, transgenic mice overexpressing pulmonary GM-CSF (SPC-GM-CSF+/+) were used to determine the effects of chronic exposure to increased pulmonary GM-CSF (without smoke inhalation) on accumulation and activation of AMs, pulmonary matrix metalloproteinase (MMP) expression and activity, lung histopathology, development of polycythemia, and survival. In WT mice, smoke exposure markedly increased pulmonary GM-CSF and AM accumulation. In unexposed SPC-GM-CSF+/+ mice, AMs were spontaneously activated as shown by phosphorylation of STAT5 (signal inducer and activator of transcription 5) and accumulated progressively with involvement of 84% (interquartile range, 55–90%) of the lung parenchyma by 10 months of age. Histopathologic features also included scattered multinucleated giant cells, alveolar epithelial cell hyperplasia, and mild alveolar wall thickening. SPC-GM-CSF+/+ mice had increased pulmonary MMP-9 and MMP-12 levels, spontaneously developed emphysema and secondary polycythemia, and had increased mortality compared with WT mice. Results show cigarette smoke increased pulmonary GM-CSF and AM proliferation, and chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP, including AM accumulation, emphysema, secondary polycythemia, and increased mortality in mice. These observations suggest pulmonary GM-CSF may be involved in the pathogenesis of DIP.

GM-CSF (granulocyte/macrophage colony-stimulating factor) is a cytokine that regulates the survival, proliferation, differentiation, and function of alveolar macrophages (AMs) (13). Overexpression of pulmonary GM-CSF from a surfactant protein C (SPC) promoter-driven transgene in the murine airway epithelium (i.e., SPC-GM-CSF+/+ transgenic mice) results in proliferation of AMs and proliferation and hyperplasia of alveolar epithelial type II cells (4, 5). GM-CSF also stimulates macrophages to secrete matrix metalloproteinases (MMPs), which have been implicated in the degradation of extracellular matrix (68) in the pathogenesis of emphysema. In humans, exposure to inhaled cigarette smoke increases pulmonary GM-CSF levels (6, 9, 10) as well as the number of AMs (11, 12) and alters AM functions (13, 14). This constellation of GM-CSF–stimulated histopathological, cellular, and molecular events suggested to us that GM-CSF might be implicated in the pathogenesis of desquamative interstitial pneumonia (DIP).

DIP was first described in 1965 (15) as a diffuse, pulmonary alveolar-filling disease initially believed to result from desquamation of alveolar epithelial cells (15, 16) but ultimately shown to result from the accumulation of AMs (17). Although classified as an interstitial pneumonia (18), DIP is characterized histologically by accumulation of macrophages and multinucleated giant cells in alveolar spaces, alveolar type II cell hyperplasia, and emphysema in the absence of extensive marked fibrosis or neutrophilic inflammation (15, 19, 20). The abnormally accumulated macrophages exhibit functions typical of normal AMs (21) and contain granular cytoplasmic pigment characteristic of cigarette smoke exposure (22).

DIP is a rare lung disorder that commonly presents as exertional dyspnea of insidious onset and persistent, nonproductive cough in male smokers between the ages of 40 and 60 years (16, 17, 19, 2325). The chest radiograph is often normal or shows only nonspecific abnormalities, and high-resolution computed tomography typically shows ground-glass opacities and centrilobular nodules with lower-lobe predominance, which is difficult to distinguish from other interstitial lung diseases (26, 27). DIP is strongly associated with smoking—most series report an association of DIP with smoking between 60% and 90% (17, 23, 28, 29)—and smoking is widely believed to be causative. Notwithstanding, a pathogenic mechanism linking cigarette smoke exposure to development of DIP has not been identified.

We hypothesized that smoke inhalation exposure would increase pulmonary GM-CSF levels and AM accumulation in wild-type (WT) mice and that transgenic mice with increased pulmonary GM-CSF expression (SPC-GM-CSF+/+) may recapitulate the cardinal features of DIP. We tested this hypothesis in SPC-GM-CSF+/+ and age-matched control mice by measuring AM accumulation, MMP expression and activity, parenchymal lung tissue damage and the development of emphysema, secondary systemic effects of chronic lung disease (polycythemia), and survival. Results support the concept that abnormally increased pulmonary GM-CSF signaling may play a role in the pathogenesis of DIP.

Animals

C57BL/6 mice (hereafter, WT mice) were purchased from Charles River. SPC-GM-CSF+/+ transgenic mice constitutively overexpressing pulmonary GM-CSF were previously described (4). All mice were bred, housed, and studied the vivarium at the Cincinnati Children’s Research Foundation or University of Cincinnati Medical School using protocols approved by the Institutional Animal Care and Use Committee.

Smoke Exposure

Mice underwent chronic cigarette smoke inhalation exposure using a TE-10z smoke generator and whole-body exposure chamber (Teague Enterprises) with 3R4F Kentucky Reference Cigarettes (University of Kentucky) as described (30). Briefly, mice were first acclimated by exposure to filtered air for 1 week and then exposed to cigarette smoke at a total suspended particulate level of 150 mg/m3 for 4 hours per day, 5 days per week, for up to 18 months. Age-matched filtered air–exposed mice served as controls.

BAL Cell and Fluid Isolation

Respiratory tract epithelial lining fluid and nonadherent cells were collected from mice by BAL using five sequential 1-ml aliquots of PBS plus 0.5 mM EDTA as described (2), which were pooled, and the recovered volume recorded. Cells were collected from BAL by centrifugation (280 × g, 10 min, 4°C). The supernatant was removed, the cell resuspended in Dulbecco’s Modified Eagle medium supplemented with 10% FBS, and AMs were isolated by adherence to tissue culture plastic and enumerated using a hemocytometer. AMs and BAL fluid were then evaluated as described below.

GM-CSF Receptor Signaling

AMs were isolated by BAL from WT or SPC-GM-CSF+/+ mice, and GM-CSF receptor signaling was measured using the STAT5 (signal transducer and activator of transcription 5) Phosphorylation Assay as previously reported (31). Briefly, AMs were evaluated by Western blotting to measure total STAT5, phosphorylated STAT5, or relative cell number by using as primary antibodies anti-STAT5 antibody (Santa Cruz Biotechnology), anti–phospho-STAT5 antibody (Millipore), or anti-actin antibody (Santa Cruz Biotechnology).

Lung Histopathology and Immunohistochemistry

Lung histology was evaluated as previously described (32). Briefly, after intraperitoneal pentobarbital administration and exsanguination by aortic transection, the trachea was exposed ventrally, cannulated through a rostral transverse incision, and cold fixative (PBS, pH7.4, containing 4% [vol/vol] paraformaldehyde) was infused at 25 cm of water pressure and closed tightly by ligation while decannulating. The heart, lungs, and trachea were removed en bloc and submerged in fixative and kept at 4°C for 24 hours. The lung lobes were removed individually, cut along the long axis into 2-mm-thick slices, washed in cold PBS, dehydrated, and embedded in paraffin, and 5-μm-thick sections were cut and stained with hematoxylin and eosin (H&E), or Masson’s trichrome as described previously (33). Lung sections were stained for CD68 using a rat anti-CD68 monoclonal antibody (FA-11; Abcam). Lung sections were examined using a Zeiss Axioplan 2 microscope (Zeiss) and AxioVision software (Zeiss).

Morphometry

Parenchymal lung tissue damage was measured by light microscopic examination of the tissue sections using a point counting–based morphometry method as previously described (33).

MMP mRNA Levels

Total RNA was isolated from AMs, purified, and used to measure mRNA transcript abundance by qRT-PCR and gene-specific oligonucleotide primers as previously described (31).

MMP Activity

BAL fluid was analyzed by gelatin zymography to measure MMP-9 activity (ThermoFisher Scientific) as previously described (33). AMs were analyzed by casein zymography to measure MMP-12 activity (ThermoFisher Scientific) as previously described (33).

Hematology

Blood was collected from 8- to 9-month-old age-matched WT and SPC-GM-CSF+/+ mice, and hemoglobin, hematocrit, and red blood cell numbers were measured on a Hemavet 850 (Drew Scientific). Serum erythropoietin was measured by ELISA (Mouse Quantikine Kit; R&D Systems).

Survival Analysis

Mice were monitored daily.

Statistical Analyses

Numeric data were evaluated for a normal distribution using Shapiro-Wilk normality test and represented as the mean ± SEM for each group or time point. For comparison of two groups, parametric (t test) or nonparametric (Mann-Whitney test) tests were done where appropriate, and P values < 0.05 were considered statistically significant. Statistical analysis was performed using GraphPad Prism 7 software.

Smoke Exposure Causes Increased Pulmonary GM-CSF and AM Accumulation

To determine the effects of smoking on AM accumulation, WT mice were exposed to cigarette smoke or filtered air (as an inhalation exposure control) and AMs were enumerated as described in the methods. Compared with age-matched filtered-air control mice, cigarette smoke–exposed mice had a fivefold increase in pulmonary GM-CSF mRNA transcript levels (Figure 1A) and a marked increase in the number of AMs at all times evaluated (Figure 1B). Macrophages constituted more than 92% of all BAL cells at all ages in WT and smoke-exposed mice. Thus, cigarette smoke exposure increased pulmonary GM-CSF and AM accumulation in mice.

Chronically Increased Pulmonary GM-CSF Causes Progressive AM Accumulation and DIP-Like Lung Histopathology

Next, we evaluated the effect of chronically increased pulmonary GM-CSF levels on AM accumulation in the absence of exposure to smoking by enumerating AMs in SPC-GM-CSF+/+ mice. Compared with age-matched WT control mice, SPC-GM-CSF+/+ mice had fourfold more AMs (Figure 2A). In addition, phosphorylated STAT5 was readily detected in AMs from SPC-GM-CSF+/+ mice, consistent with constitutively increased GM-CSF receptor signaling in these mice, but was not detected in WT mice (Figure 2B).

Microscopic examination confirmed the progressive AM accumulation in SPC-GM-CSF+/+ mice, which involved 84% (interquartile range, 55–90%) of the lung parenchyma by 10 months of age and included complete filling of most alveoli, partial filling of alveolar ducts, and spilling into terminal bronchioles (Figures 3A–3F). Histopathologic findings did not include gross alveolar distortion due to fibrosis (Figures 3G–3I) but did include progressive alveolar dropout (compare Figures 3D–3I with Figures 3A–3C), mild thickening of alveolar walls (Figure 3J), alveolar epithelial cell hyperplasia (Figure 3K), and the presence of multinucleated giant cells in a scattered distribution (Figure 3L). The thickening of alveolar walls was due primarily to accumulation of CD68+ macrophages in SPC-GM-CSF+/+ compared with WT mice (Figures 3M–3O) and a very mild increase in intraseptal fibrosis in some but not all older mice (Figure 3I). Together, these results demonstrate that exposure to inhaled cigarette smoke caused an increase in pulmonary GM-CSF expression and AM accumulation and that constitutive overexpression of pulmonary GM-CSF in the absence of smoke exposure stimulated GM-CSF receptor signaling in AMs and resulted in progressive and marked accumulation of AMs, emphysematous change, and mild increase in septal fibrotic tissue accumulation, histopathology features strikingly similar to those observed in human patients with DIP.

Chronically Increased Pulmonary GM-CSF Causes AM Metalloprotease Expression and Alveolar Wall Damage

Because cigarette smoke and GM-CSF can both stimulate AMs to express destructive proteases, we examined MMP-9 and MMP-12 expression and found AMs from SPC-GM-CSF+/+ mice had an 11-fold increase in MMP-9 mRNA and a threefold increase in MMP-12 mRNA compared with respective levels in age-matched WT control mice (Figures 4A and 4C). The bioactivity of MMP-9 and MMP-12 was increased by more than 13-fold and 18-fold, respectively, in AMs from SPC-GM-CSF+/+ mice compared with age-matched WT control mice (Figures 4B and 4D). Morphometric measurement of parenchymal lung tissue density showed the fractional area of lung-composing tissue was reduced in 10-month-old SPC-GM-CSF+/+ mice compared with age-matched WT mice (23.6 ± 1.8% vs. 41.1 ± 1.5%, respectively; P < 0.0001) (Figure 4E). These results demonstrate that constitutive overexpression of pulmonary GM-CSF resulted in expression of proteases by AMs and loss of parenchymal lung tissue.

Chronic Lung Disease in SPC-GM-CSF+/+ Mice Is Associated with Polycythemia

Because hypoxemia resulting from chronic lung disease can cause secondary systemic effects such as polycythemia, we measured hemoglobin, hematocrit, and red blood cell number and found that all three were increased in SPC-GM-CSF+/+ mice compared with age-matched WT control mice at 9 months of age (19.2 ± 0.9 vs. 12.4 ± 0.5 g/dl, 65.3 ± 3.5 vs. 42.5 ±1.6%, 12.25 × 106 vs. 8.75 × 106 red blood cells/μl, respectively; n = 10–11 mice/group; P < 0.0001) (Figures 5A–5C). Consistent with the increase in red cell mass, SPC-GM-CSF+/+ mice had a sixfold increase in serum erythropoietin compared with age-matched WT mice (Figure 5D). These results demonstrate SPC-GM-CSF+/+ mice develop polycythemia in association with the development of DIP-like chronic lung disease.

Chronic Lung Disease in SPC-GM-CSF+/+ Mice Is Associated with Increased Mortality

Because the progressive filling of alveoli with AMs, damage to lung parenchyma, and secondary polycythemia in SPC-GM-CSF+/+ mice all suggested lung function was severely compromised, we evaluated overall survival. SPC-GM-CSF+/+ mice had increased mortality that was evident by 6 to 8 months of age, increased progressively thereafter, and by 16 months resulted in a survival rate of 24% in SPC-GM-CSF+/+ mice compared with 84% in age-matched WT control mice (Figure 6). The increase in mortality reduced the median survival of SPC-GM-CSF+/+ mice to 10.5 months.

In this study, we showed in mice that chronic exposure to inhaled cigarette smoke caused increased pulmonary GM-CSF and progressive alveolar macrophage accumulation and that chronic exposure to increased pulmonary GM-CSF without exposure to cigarette smoke caused progressive alveolar macrophage accumulation and activation with increased expression of MMP-9/MMP-12, parenchymal lung damage resulting in emphysema, secondary polycythemia, and increased mortality. Histopathological abnormalities were diffuse, progressive, and comprised alveolar damage/dropout, filling of alveoli with AMs and occasional multinucleated giant cells, alveolar wall thickening due to an increase in AMs, epithelial cell hyperplasia, and minimal to no fibrosis.

The observation that cigarette smoking increased pulmonary GM-CSF and that chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP suggests GM-CSF might play a role in the pathogenesis of DIP. Various clinical conditions have been reported in association with DIP, including connective tissue diseases (34, 35), lung infection (36, 37), drugs (38), and inorganic dust exposure (20, 29, 39), although no pathogenic mechanisms have been identified. DIP can also occur as a minor or “secondary” histopathologic feature of various other lung diseases, suggesting it may be a reactive macrophage accumulation process rather than the primary disease process. Together, our results and these previous reports suggest DIP may be a “final common response pathway” that can be initiated in various contexts and results in chronically increased pulmonary GM-CSF signaling, either due to increased GM-CSF secretion or sensitivity or reduced extinction of normally initiated signaling. We propose a mechanism (Figure 7) by which DIP is driven by the following axis of pathogenesis: smoke inhalation (or another initiator)→pulmonary GM-CSF hypersecretion response→AM accumulation and activation→MMP secretion→parenchymal lung damage→emphysema→secondary polycythemia→increased mortality. Alternatively, increased GM-CSF signaling could be caused by increased responsiveness to normal GM-CSF secretion response or to reduced extinction of a normally initiated GM-CSF secretion response. In either case, presumably, the abnormal response might result from a genetic abnormality involving the GM-CSF signaling response pathway.

Although pulmonary GM-CSF concentration is normally very low or undetectable, its presence is required for regulation of AM differentiation, population size, and functions critical to surfactant homeostasis, alveolar stability, lung function, and host defense (2, 3, 32, 40, 41). GM-CSF regulates macrophage-mediated cholesterol clearance in constitutive, reversible, and dose-responsive fashion (42). Disruption of pulmonary GM-CSF signaling in humans (4346), nonhuman primates (47, 48), and mice (40, 49) reduces the number of functional AMs and results in the development of pulmonary alveolar proteinosis. The present study demonstrates that chronically increased pulmonary GM-CSF in mice results in an “opposite” lung phenotype: increased numbers of functionally hyperactive AMs, progressive lung damage, and a lung phenotype identical to DIP. These results indicate maintaining pulmonary GM-CSF at a low but nonzero concentration is critically important and suggests GM-CSF functions more as a pulmonary hormone than a proinflammatory cytokine.

The limitations of our study include that it did not determine a dose–response relationship between pulmonary GM-CSF concentration and the degree of alveolar macrophage accumulation and/or activation, the minimum increase in pulmonary GM-CSF necessary to stimulate abnormal alveolar macrophage accumulation, or the maximum time that pulmonary GM-CSF could be increased without causing irreparable parenchymal lung damage. Nor did it translate the observations in mice to humans, which will require future studies to examine the role or presence of GM-CSF in the lungs of humans with DIP. Notwithstanding, results demonstrate the utility of SPC-GM-CSF+/+ mice for studying the effects of excess pulmonary GM-CSF signaling on AM accumulation and function as well as the role of GM-CSF in lung health. Our results suggest a new mechanistic approach to explore the pathogenesis of DIP in humans. If the pulmonary GM-CSF signaling response is increased in DIP, SPC-GM-CSF+/+ mice may be useful to further explore the pathogenesis of DIP.

The authors thank Dr. Robert Senior (Washington University, St. Louis) for assistance with smoke exposure experiments and Dr. Rhonda Szczesniak (Cincinnati Children’s Hospital) for statistical advice.

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Correspondence and requests for reprints should be addressed to Bruce C. Trapnell, M.D., Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. E-mail: .

*Co–first authors.

Supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant R01 HL085453 (B.C.T.) and National Center for Advancing Translational Science/National Heart, Lung, and Blood Institute grant U54 HL127672 (B.C.T.).

Author Contributions: T.S., C.M., and B.C.T. designed the study. T.S., C.M., B.C.C., M.B., D. Beck, K.A.W.-B., D. Black, and C.C. performed research and analyzed data. T.S., C.M., and B.C.T. wrote the manuscript. T.S., C.M., B.C.C., M.B., D. Beck, K.A.W.-B., D. Black, C.C., and B.C.T. revised and approved the final manuscript.

This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Originally Published in Press as DOI: 10.1165/rcmb.2018-0294OC on July 16, 2019

Author disclosures are available with the text of this article at www.atsjournals.org.

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