## 2 Lower Respiratory Microenvironment
### Lower Respiratory Extracellular Matrix Composition and Role
#### 2.2.2 Pulmonary Extracellular Matrix Composition in Disease  
Pulmonary ECM proteins are associated with branching, angiogenesis, alveolar maturation, tissue repair after injury as well as pathological processes leading to acute and chronic lung diseases such as asthma, COPD, and IPF [26]. Recent studies have shown that damage to elastin fibers upon increased fibronectin and tenascin levels in COPD airways alters ECM stiffness [27]. Similarly, a high level of collagen deposition in fibrotic disorders (e.g., IPF) is associated with a marked increase in lung stiffness [28]. The ECM in normal lungs forms a loose network of fibronectin, collagen, and elastin \begin{table}
\begin{tabular}{c c c c} \hline \hline \multicolumn{2}{c}{**ECM Glycoprotein**} & **Collagens** & **Proteoglycans** \\ \hline
543041901781K & LIG3 & COLL0A1 & ACAN \\ ABISW & LTBP1; LTBP3; LTBP4 & COLL1A1; LT2A & ASPN \\ ADIPOQ & MATNI; MATNI2; MATNI4 & COLL2A1 & BGN \\ AEPI & MFA2P2; MEAP4; MEAP5 & COLL3A1 & CHAD \\ AGN & MFGS & COLL4A1 & DCN \\ AW551984 & MGP & COLL5A1 & PAGD \\ BMPER & MMB1; MMRN2 & COLL6A1 & HAPLIN1 \\ CLP & NDN & COLL7A1 & HAPLIN3 \\ CLP2 & NDN1; NID2 & COLL8A1 & HAPLIN4 \\ COLO & NNTN & COLL9A1 & HSPC2 \\ COMP & NTN; NTN2; NTN4 & COLL1A1; IA2 & MPGI \\ CRSPID2 & PAPIN & COLL2A1 & LIM \\ DFT & FCOLCE; FOCLC2 & COLL3A1 & GGN \\ ECM1; ECM2 & POSTN & COLL2A1 & PODN \\ EFEMT; EFEMT2P2 & PXDN & COLL2A1 & PREL2 \\ EGERERER & RELN & COLL2A1 & PRG2 \\ ELN & SBSFON & COLL2A1 & PRG3 \\ EMD1 & SLITS & COLL2A1 & VCAN \\ EMILIN; EMILN2 & SNED1 & COLL3A1 & \\ FUNI; FUNI; FUN2; FUNS & SPARC; SPARCL1 & COLL4A1; 2; 3; 4; 5; 6 & \\ FFNI; FFN2 & SPON & COLL5A1; 5A2; 5A3 & \\ FGA; PGR; FGG & SPBY; SPRQ2 & COLL4A1; 2; 3-4; 5; 6 & \\ FGL2 & SVP1 & COLL7A1 & \\ FNI & TCFBI & COLL8A1; A2 & \\ FRASI & THBS1; THBS2; THBS3 & COLL9A1; 9A2; 9A3 & \\ GLDN & THSD4 & THSD4 & \\ HMCN1; HMCN2 & THANG; TNAG1 & \\ KFALS & TNC; TNXB & \\ KFPRG; ICFBP7 & VTN & \\ KSF10 & WWAI; 3A; 5A; 5B1; A9 & \\ LKCP & VWF & \\ LAMA1; A2; A3; A4; A5; B1; B2; B3; C1; C2; C3 & WEP2 & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Composition of the pulmonary extracellular matrix (ECM). Reproduced with permission from [26]. Copyright © 2018 Elsevier. that is maintained by the activity of fibroblasts and that adheres to the basement membrane of the epithelial cell layer. However, the properties of the pulmonary ECM show substantial changes under diseased condition. The following describes pathological changes of the pulmonary ECM in lung disease. (1) In IPF, fibroblasts are converted to myofiboblasts, which deposit pulmonary ECM proteins into the cytoplasm, and increased collagen-elastin enzymatic covalent crosslinking dramatically enhances pulmonary ECM stiffness. (2) In COPD, a characteristic pathological change in the pulmonary ECM is the extensive destruction of elastic fibers by ECM-degrading enzymes released by inflammatory cells. This increases levels of hyaluron and tenascin C and decreases the deposition of decorin, and destruction of the epithelial cell layer results in air space expansion (pulmonary emphysema). (3) In pulmonary arterial hypertension (PAH), remodeling of the ECM in the arterial wall is characterized by an increase in elastin and collagen, fibronectin, tenascin C, and the proliferation of smooth muscle cells (SMCs). (4) In asthma, pulmonary ECM alterations and enrichment occur below the bronchial epithelial basement membrane, SMCs proliferate and increase their deposition of collagen, fibronectin, hyaluron, and decorin. (5) In cancer, TGF\(\beta\) function is modulated by the decorin and Syndecan-4, and it drives proinvasive EMT in cancer cells, and conversion of stromal fibroblasts to contractile cancer-associated fibroblasts (CAFs). CAFs modulate collagen matrix stiffness via interactions through integrins, and matrix stiffness also affects mobility of tumor-infiltrating leukocytes (TILs).