Myofibroblasts are increased in the lung parenchyma in asthma

<div><p>Background</p><p>Increased airway smooth muscle is observed in large and small airways in asthma. Semi-quantitative estimates suggest that cells containing alpha smooth muscle actin (α-SMA) are also increased in the lung parenchyma. This study quantified and characterized α-SMA positive cells (α-SMA+) in the lung parenchyma of non-asthmatic and asthmatic individuals.</p><p>Methods</p><p>Post-mortem sections of peripheral lung from cases of fatal asthma (FA), persons with asthma dying of non-respiratory causes (NFA) and non-asthma control subjects (NAC) were stained for α-SMA, quantified using point-counting and normalised to alveolar basement membrane length and interstitial area.</p><p>Results</p><p>α-SMA+ fractional area was increased in alveolar parenchyma in both FA (14.7 ± 2.8% of tissue area) and NFA (13.0 ± 1.2%), compared with NAC (7.4 ± 2.4%), p < 0.05 The difference was greater in upper lobes compared with lower lobes (p < 0.01) in both asthma groups. Similar changes were observed in alveolar ducts and alveolar walls. The electron microscopic features of the α-SMA+ cells were characteristic of myofibroblasts.</p><p>Conclusions</p><p>We conclude that in asthma there is a marked increase in α-SMA+ myofibroblasts in the lung parenchyma. The physiologic consequences of this increase are unknown.</p></div

Demographic characteristics of the study population: Fatal asthma (FA), non-fatal asthma (NFA) and non-asthma control (NAC) patients.

<p>(n = 7, all groups).</p

Alveolar wall thickness normalized to basement membrane length (um) by group.

<p>Alveolar wall thickness normalized to basement membrane length (um) by group.</p

Area of alpha smooth muscle actin (α-SMA) staining in alveolar ducts, alveolar walls and blood vessels as a percentage of total parenchyma by group.

<p>Area of alpha smooth muscle actin (α-SMA) staining in alveolar ducts, alveolar walls and blood vessels as a percentage of total parenchyma by group.</p

Area of α-SMA staining (normalized to basement membrane length) in alveolar ducts (blue) and alveolar walls (red hatched) of upper and lower lobes from cases of fatal asthma (FA) and non-fatal asthma (NFA), and from non-asthma control subjects (NAC).

<p>† p < 0.05 for alveolar ducts for both upper and lower lobes. ‡ p < 0.05 for alveolar walls for upper lobe only. # p < 0.01 upper vs lower lobes.</p

Myofibroblasts are increased in the lung parenchyma in asthma - Fig 2

<p>Examples of light micrographs from cases of non-asthma control (NAC) (A&B)and cases of fatal asthma (FA) (C,D,E&F) stained for alpha-smooth muscle actin. In the NAC case, the majority of the smooth muscle actin staining is seen in the alveolar duct tip (arrows) where it is concentrated with more subtle staining in the alveolar walls. By comparison, the FA case shows greater quantities of actin staining in the alveolar duct tip (arrow) with an even greater increase in alpha-smooth muscle actin staining in the alveolar walls (C-F arrowheads). At higher magnification (E,F) in addition to α-SMA + staining of the cell bodies there are α-SMA + cytoplasmic extensions of these cells into the adjacent interstitium providing a dendritic appearance (arrows).</p

Baseline characteristics of cohort studies included in the meta-analysis^*.

<p><i>Definition of abbreviations</i>: ARIC  =  Atherosclerosis Risk in Communities; B58C  =  British 1958 Birth Cohort; BHS  =  Busselton Health Study; CARDIA  =  Coronary Artery Risk Development in Young Adults; CHS  =  Cardiovascular Health Study  =  FHS, Framingham Heart Study; Health ABC  =  Health, Aging, and Body Composition; KORA  =  Cooperative Health Research in the Region of Augsburg; LBC1921  =  Lothian Birth Cohort 1921; LBC1936  =  Lothian Birth Cohort 1936; PIVUS  =  Prospective Investigation of the Vasculature in Uppsala Seniors; RS  =  Rotterdam Study; SAPALDIA  =  Swiss Study on Air Pollution and Lung Diseases in Adults; SD  =  standard deviation; SHIP  =  Study of Health in Pomerania.</p><p>^*Data are presented as mean (SD) unless otherwise indicated; total no. participants  =  27,249, total no. FEV₁ measurements  =  62,130.</p>†<p>Pack-years are calculated among current and former smokers at study baseline.</p

Association of the chromosome 11 locus with the rate of change in FEV₁ in the meta-analysis of the five cohort studies with ≥3 FEV₁ measurements per participant.

<p><b>A</b>) Regional association plot, where the X-axis is Megabase (Mb) position, and the Y-axes are the negative log of the <i>P</i> value on the left and recombination rate on the right. The sentinel SNP is colored in purple and linkage disequilibrium to the sentinel SNP is depicted by degree of color according to the legend. <b>B</b>) Forest plot for rs507211, where the size of the square for each study represents its contributing weight to the meta-analysis.</p

Association of the chromosome 15 locus with the rate of change in FEV₁ in the meta-analysis of 14 cohort studies.

<p><b>A</b>) Regional association plot, where the X-axis is Megabase (Mb) position and Y-axes are the negative log of the <i>P</i> value on the left and recombination rate on the right. The sentinel SNP is colored in purple and linkage disequilibrium to the sentinel SNP is depicted by degree of color according to the legend. <b>B</b>) Forest plot for rs4077833, where the size of the square for each study represents its contributing weight to the meta-analysis.</p

Association of the most statistically significant SNPs with the rate of change in FEV₁ (mL/year) in the meta-analysis of 14 cohort studies (n = 27,249)^*.

<p><i>Definition of abbreviations</i>: Chr  =  chromosome; SE  =  standard error; SNP  =  single-nucleotide polymorphism.</p><p>^*Data reported are the meta-analysis results of the SNP-by-time interaction term from the GWAS mixed effects model. A positive β-coefficient indicates an attenuation of FEV₁ decline and a negative β-coefficient an acceleration of FEV₁ decline.</p