# Sex-Based Differences in Bronchial Asthma: What Are the Mechanisms behind Them?
## 3 Endotypes and Phenotypes of Bronchial Asthma
In the mixed granulocyte endotype of asthma, both allergic-dependent and allergic-independent mechanisms may occur hand in hand, leading to mixed granulocyte inflammation [1]. The pathophysiological characteristics of the main endotypes of asthma are summarized in Table 1.  
Differences in the pathophysiological backgrounds of the major asthma endotypes not only result in different diagnostic criteria for individual types of asthma but may also be responsible for variations in the appropriate treatment [2; 10; 11; 12; 13]. For instance, eosinophil subtypes of asthma usually respond well to corticosteroids [12; 14], while both non-eosinophilic subtypes of asthma are insensitive to corticosteroids and, therefore, novel treatments have been intensively studied [13]. \begin{table}
\begin{tabular}{l c c c c c} \hline  & \multicolumn{2}{c}{**Eosinophilic Asthma**} & \multicolumn{2}{c}{**Non-Eosinophilic Asthma**} & \multicolumn{2}{c}{**Mixed Granulocytic Asthma**} \\ \hline  & **Allergic** & **Non-allergic** & **Paucigranulocytic** & **Neutrophilic** & \\ \hline \multirow{2}{*}{Triggering agents} & \multirow{2}{*}{Allergens} & Pollutants, & Pollutants, & Pollutants, & \\  & & microbes & oxidative stress & & oxidative stress, \\ \hline Involvement of eosinophils & ++ & ++ & \(-\) & \(-\) & \(+\) \\ \hline Sputum eosinophils & \(>\)3\% & \(>\)3\% & \(<\)3\% & \(<\)3\% & \(>\)3\% \\ \hline Blood eosinophils & \(+\) & \(+\) & \(-\) & \(-\) & \(-\) \\ \hline Atopy & \(+\) & \(-\) & \(-\) & \(-\) & \(-\) \\ \hline Involvement of neutrophils & \(-\) & \(-\) & \(-\) & \(++\) & \(+\) \\ \hline Sputum neutrophils & \(<\)61\% & \(<\)61\% & \(<\)61\% & \(\geq\)61\% & \(\geq\)61\% \\ \hline Epithelial damage & \(++\) & \(++\) & \(+\) & \(++\) & \(++\) \\ \hline Mucus & \(+\) & \(+\) & \(+/-\) & \(++\) & \(++\) \\ \hline Reticular membrane & \(++\) & \(++\) & \(+/-\) & \(+\) & \(+\) \\ basement thickening & \(++\) & \(++\) & \(+/-\) & \(+\) & \(+\) \\ \hline Airway smooth muscle & \(++\) & \(++\) & \(+\) & \(+\) & \(+\) \\ \hline \end{tabular} Notes: \(++\): high increase, \(+\): moderate increase, \(+/-\): inconsistent changes, \(-\): no increase.  
\end{table} 
Table 1: Features of major asthma endotypes (modified from [1; 2; 3; 8]). A review of clinical and biochemical biomarkers for eosinophil, neutrophil, and paucigranulocytic asthma is provided in Table 2, and currently available and promising treatments are listed in Table 3. \begin{table}
\begin{tabular}{l c c c} \hline \hline  & **Eosinophilic Asthma** & **Neutrophilic Asthma** & **Paucigranulocytic Asthma** \\ \hline FeNO & ++ & +/ \(-\) & + \\ \hline AHR & ++ & +/ \(-\) & + \\ \hline \multirow{4}{*}{Endotype-specific changes in biochemical biomarkers} & \(\uparrow\) serum periostin & \(\uparrow\) serum CRP and IL-6 \\  & \(\uparrow\) serum IgE (in atopy) & \(\uparrow\) sputum supernatant IL-8, IL-17, MPO, \\  & \(\uparrow\) sputum supernatant ECD, EDN, & NE, TNF\(\alpha\), CXCR1, and CXCR2 \\  & EPO, eotaxin-2, IL-5, IL-13, & \(\downarrow\) sputum gal-3 \\  & GM-CSF, osteepontin, & \(\uparrow\) gal-3 BP and IL-1ß \\  & angiopoietin-I, Grx1; \(\uparrow\) MMP-9 & \(\downarrow\) gal-3/ gal-3 BP and IL-1 Ra/IL-1ß \\ \hline \multirow{4}{*}{Endotype-specific changes in biochemical biomarkers} & \multicolumn{1}{c}{Abbreviations: AHR: airway hyperresponsiveness, CRP: C-reactive protein, CXCR: chemokine (C-X-C motif) receptor, EXP: eosinophil cationic protein, EDN: eosinophil-derived neurotoxin, EPO: eosinophil peroxidase, FeNO: fractional exhaled nitric oxide, gal-3: galectin-3, gal-3 BP: galectin-3 binding protein, GM-CSF: granulocyte-macrophage colony-stimulating factor, Grx1: glutaredoxin 1, IgE: immunoglobulin E, IL: interleukin, IL-1 Ra: interleukin-1 receptor antagonist, MMP: matrix metalloproteinase, MPO: myeloperoxidase, NE: neutrophil elastase, TNF\(\alpha\): tumor necrosis factor alpha, ++: high increase, +: moderate increase, +/\(-\): low values, \(\uparrow\): increase, \(\downarrow\): decrease.} \\ \hline \hline \end{tabular}
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